MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/ONKOLOGIE/melanom/zlepsujici-podpurne-vlivy

Varování

  • The majority of studies cited are in vitro studies, performed in glass on tissue from a living organism, or in vivo studies, performed on tissue not removed from a living organism (animal studies).
  • Most studies have not advanced to clinical trials on humans.
  • The few human studies cited are preliminary clinical trials.
  • Therefore, although results seem favorable or unfavorable, treat them with caution.
  • Neither the author nor publisher makes any medical claims for any of the herbs or natural products in this review or the tables.
  • This are just study notes
  • Note that some of the herbs described are deadly poisons and extremely dangerous.
  • Vybírat jen netoxické věci, zhodnotit dávkování a dostupnost v ČR
    • Je fajn, že naprostá většina dohledaných věcí toto splňuje - horší je to s volbou správné dávky, aby byla efektivní

ADI-PEG20

  • Terapie deprivací argininu;
    • Melanom, rakovina jater

Alfacyklodextriny

  • Snižují cholesterol a další lipidické látky, tak by to mohlo něco dělat
  • Dohledat

Aspirin

  • Podobně jako kurkumin ve vyšších dávkách stimuluje demetylaci DNA (může přispět k apoptoze), a inhibuje COX (blokáda jedné z cest angiogeneze)
  • Tak by se mohl také uplatnit
  • Dohledat

Ati PD-1/PD-L1 ligandy

  • U psů přinesla první klinické výsledky pilotní studie blokády indukce programované buněčné smrti protinádorových T lymfocytů (dráha PD-1/PD-L1), která je aktivována v důsledku aberantní exprese ligandu PD-L1 na povrchu nádorových buněk.
  • U některých lidských pacientů regresi zhoubného nádoru
  • Může způsobovat aberantní imunitní aktivaci vedoucí k nežádoucímu zánětu a autoimunitním reakcím

Pembrolizumab

  • Proti PD-1

Nivolumab

Ipilimumab

Monoklonální protilátky proti disialogangliosidům

Bakteriální antigeny nebo jejich deriváty

Onkolytická viroterapie

Vakcíny založené na autologních dendritických buňkách

  • Efektorovým složkám imunitního systému prezentují nádorově specifické antigeny
  • Od prezentace specifických peptidů přes použití nádorových lyzátů až po transfekci DC za použití mRNA kódující nádorové antigeny.
  • Účinná aktivace T-buněčné odpovědi proti nádorovým antigenům byla prokázána na souboru zdravých psů
    • Pomocí opožděné hypersenzitivní kožní reakce (DTH – delayed type hypersensitivity)
  • Další možností je očkování celobuněčnou vakcínou.
  • Technická a časová náročnost její přípravy však limituje její produkci v dostatečném množství a kvalitě.

  • Někde na téhle úrovni by mohl fungovat podvaz povrchového nádoru

Bacille Calmette-Guerin (BCG) vaccine

Baicalin - Sišák bajkalský



Betaglukany

  • Dohledat

Bortezomib + Clarithromycin

Brokolice

  • A sulfuraphan

Suppression of COX-2 and PI3K/AKT

  • The PI3K/AKT, NFjB and COX-2 pathways
    • Involved in the radioprotective response
      • Highly active in melanoma cells
  • Substantially increased G2/M arrest
    • Decreased clonogenic survival of gamma-irradiated melanomas
      • Predominantly via a necrotic mechanism (Fulda and Debatin, 2004)
  • Například resveratrolem ale nebo taky coxiby (meloxicam aj.)

Chrysin from acacia honey

Cisplatina

  • The most potent anticancer properties of coumarins were presented by osthole and xanthotoxol.
    • Lowest median inhibitory concentration (IC50) values relative to the FM55P and FM55M2 melanoma cells
  • Isobolographic analysis showed that for both melanoma cell lines, the combination of CDDP and osthole exerted synergistic and additive interactions
  • Combination of CDDP and xanthotoxol exerted additive interactions.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7827586/
  • Hlavní doporučení během chemoterapie platinovými deriváty

Acetyl L Carnitine (během léčby mezi 2-5 gramy denně)

  • Zejména u lidí starších a trpících podváhou (van Dam, 2016)
  • Některé zdroje ALC nedoporučují pro zmírnění neuropatie
    • Na základě jedné studie, která neukázala žádný rozdíl mezi ALC a placebo po 12 týdnech a po 24 týdnech i mírné zhoršení
    • Studie ale byla u taxanových cytostatik, nikoliv u platinových derivátů (tedy u úplně jiné kategorie léků)
    • U platiny by naopak měla být suplementace prospěšná z více důvodů.

Nefrotoxicita (ledviny; velmi časté) Miller, 2010

  • Zvýšené riziko nefrotoxicity mají pacienti, kteří pravidelně užívají NSAID (aspirin, ibuprofen aj.)
  • Preventivně:
    • ALA (Kang, 2009; Bae 2009)
    • lykopen (Atessahin, 2005)
    • částečný účinek silymarinu (Karimi, 2005)
    • Doplňování hořčíku (Oka, 2014; Kidera, 2014);
      • Nedávné studie zjistily, že během podávání cisplatiny dochází k velkým úbytkům hořčíku a že doplňování hořčíku redukuje ledvinovou toxicitu během léčby. Bude dobré konzultovat s lékařem, ve studii se podávaly nitrožilní infuze hořčíku spolu s diurézou manitolem.
    • melatonin (Kilic, 2013; Sener, 2000)
    • Ginkgo biloba Song, 2013; Okuyan, 2012
    • Quercetin (Sanchez-Gonzalez 2011)

Neuropatie

  • Preventivně:
    • ALA Melli, 2008
    • Ginkgo biloba (Marshall, 2004; podávalo se 120mg orálně; malá studie 17 pacientů u kolorektálního karcinomu)

Kardiovaskulární rizika

  • Preventivně:
    • Zázvorový extrakt Attyah
      • 2012 studie na myších, pozitivní vliv na ochranu jater a srdce;
      • Zázvorový extrakt by také měl zmírňovat zvracení a může mít ochranný vliv na ledviny
    • resveratrol, l-carnitine, ALA, silymarin (Raja, 2013)
    • Thymoquinone (Adali, 2016); musí jít o nízké dávky (viz chemoterapie a synergické doplňky)

Ototoxicita (negativní vliv na sluch)

  • Preventivně:
    • melatonin (de Araujo, 2014)
    • ALA (Rybak, 1999; Kim, 2014)
    • Ginkgo biloba (Huang, 2007; Choi, 2013; Cakil, 2012; Sampaio, 2013)
    • resveratrol
      • POZOR rozporuplné výsledky redukce Erdem, 2012; Tutkun, 2012; Lee, 2015 vs u některých dávkování zvýšení ototoxicity v pokusu na myších
        • Jde zřejmě o vliv velikosti dávek. U nízkých dávek by riziko být nemělo (resveratrol v nízkých dávkách má antioxidantní působení; ve vysokých cytotoxické).

Neurotoxicita (negativní vliv na mozek)

  • Preventivně:
    • vitamín E (Pace, 2010; Savarese, 2003);
      • Klinická studie, skupina s cisplatinou + vit. E měla výskyt neurotoxicity 5,9% vs cisplatin skupina 41,7%.
        • Podával se alpha-tocopherol 400 mg/den. Nicméně doporučení je v možném rozporu s působením vitamínu E na nádorové buňky (link)
    • Acetyl-L-carnitine.
      • Jako bezpečná alternativa k vit. E Ghirardi, 2005;
      • K chemo paclitaxel+cisplatin Pisano, 2003.
      • Cisplatina způsobuje nedostatek L-karnitinu a ten pak chronickou únavu (Endo, 2015)

Zvýšení účinnosti platinových derivátů

Nevhodné kombinovat

Clotrimazole

  • FDA-approved broad-spectrum anti-mycotic drug used to treat fungal infections of the skin and vagina
    • Solution or cream
  • Affects the ergosterol synthesis of the fungus
    • Inhibition of fungal cell growth and cell wall permeability

In vivo and in vitro

  • Anticancer activity of Clotrimazole against different types of cancer such as
    • Breast, melanoma, colon, and lung tissues
  • Detachment, from the cytoskeleton, of specific glycolytic enzymes such as hexokinase, aldolase, or fructokinase
  • Ca2+-activated potassium channels also mediate Clotrimazol-induced anticancer activity
  • In vivo, a radio-sensitizing effect of Clotrimazol in melanoma
  • www.mdpi.com/2072-6694/13/13/3193/htm

Water extracts of Cordyceps sinensis (WECS) + Methotrexat

In vitro

  • WECS (100 w g/ml)
    • Induced apoptosis of B16 melanoma cells after 48 h exposure in vitro

Myši

  • WECS and methotrexate (MTX) in mice intravenously inoculated with B16 melanoma cells was conducted
    • MTX caused a significant and severe decrease in body weight compared with that in control mice starting 16 days after the start of administration
    • Mice given both MTX and WECS did not show a significant decrease in body weight
  • Mean survival time (days) of the control mice
    • MTX-treated mice (15 mg/kg/day, s.c.) 25.0 - 0.3,
    • WECS-treated mice (200 mg/kg/day, p.o.) 25.6 - 1.3
    • MTX + WECS was 28.2 - 0.7 - significantly longer
  • www.tandfonline.com/doi/abs/10.3109/713745176

Cordyceps sinensis

  • Fungus parasite that lives on caterpillars in China’s high mountain region
  • Cordyceps cells are propagated in laboratories (Robbers & Tyler, 1999)
  • Lethargy, chronic bronchitis, kidney disorders, male sexual dysfunction, anemia, liver dysfunction, and dizziness
  • Cordyceps might be cytotoxic to cancer cells (Bok, Lermer, Chilton, Klingeman, & Towers, 1999; Kuo et al., 1994; Kuo, Tsai, Shiao, Chen, & Lin, 1996), especially lung carcinoma (Nakamura et al., 1999) and melanoma (Xu, Peng, Chen, & Chen, 1992)
  • No adverse effects have been reported (Natural Medicines Comprehensive Database, 2004)
  • Zhu, Halpern, and Jones (1998) used a dose of 3 g daily.
Muriel J. Montbriand, PhD, RN; Downloaded on 08 28 2019.

  • Anti-melanogenesis in B16F0 Melanoma Cells by Extract of Fermented Cordyceps militaris Containing High Cordycepin
  • Results suggest that
    • ADP accelerated hematogenic metastasis
    • Cordycepin has an inhibitory effect on hematogenic metastasis of B16-F1 melanoma cells
      • Via blocking of ADP-induced platelet aggregation in vivo
        • Tak by možná fakt stačila kyselina acetylsalicylová, ale zjevně to nebude jediný účinek a cordiceps se bude s aspirinem a pod. dobře doplňovat...
  • Reported the augmentation of the in vivo and in vitro NK activities of the mouse.
  • Pre-incubation of peripheral blood mononuclear cells (PBMCs) with C. sinensis elevated in vitro NK activity of human PBMCs, whereas the colony formation of B16 melanoma in mouse lungs was reduced drastically.
  • CP2-S, (a novel polysaccharide) purified from C. militaris (L.) Fr.
    • Exhibits immunostimulatory activity by inducing phagocytosis, NO production, respiratory burst, and secretion of IL-1beta and IL-2 (from macrophages).
    • Bi et al. (2018) reported the immunostimulatory action of the novel polysaccharide (low-molecular-weight) obtained from the fruiting bodies (cultured) of C. militaris (L.) Fr.
      • In splenic lymphocytes and natural killer cells through induction of MAPK, NF-?B, and Toll-like receptor (TLR) two pathways.
  • Ethanol extracts of C. sinensis
    • Enhance phagocytosis activity as evidenced by carbon clearance in tumor-bearing mice.
    • It also caused a remarkable increment in an acid phosphatase activity and lysosomal enzymes in macrophages suggesting its antitumor action via the immuno-stimulating function (Shin et al., 2001; Shin et al., 2003).
  • Cordycepin
    • Inhibited the phosphorylation of protein kinase B (Akt), IkappaBalpha, and p38
    • Suppressed TNF-alpha, cyclooxygenase-2 (COX-2), iNOS, and NF-kappaB translocation in these macrophages.
  • Cordycepin for inflammation-linked disorders (Kim et al., 2006).
  • C. sinensis has been reported to strengthen the cell-mediated immunity as well (Liu et al., 2007).
  • Cordycepin exhibited an anti-cancer effect against B16 mouse melanoma
    • By inducing the adenosine A3 receptor,
    • Eventual activation of glycogen synthase kinase-3beta
    • Suppression of cyclin D1
  • Coadjuvant effect with other drugs: 2'-deoxycoformycin
    • Increased three hundred-fold the anti-cancer effect in B16 cells (Nakamura et al., 2015).
  • www.frontiersin.org/articles/10.3389/fphar.2020.602364/full

Dabrafenib

  • Inhibitor BRAF

Dacarbazin

  • Referenční chemoterapií zůstáva monoterapie dacarbazinem
  • Dacarbazin nebyl nikdy porovnán v randomizované klinické studii s optimální podpůrnou léčbou.
  • Více než 80 % nových případů onemocnění je zachyceno v lokalizovaném stadiu, což však nezaručuje trvalé vyléčení.
  • Riziko systémové diseminace kožních MM se významně zvyšuje u nemocných s prokázaným postižením regionálních uzlin.
  • V posledních třech letech došlo k výraznému posunu v účinnosti léčby metastazujícího onemocnění díky klinickému uplatnění nových léčebných přístupů, jako jsou
    • Cílená biologická léčba
    • Inovovaná imunoterapie.
  • V adjuvantní léčbě, která je podávána s kurativním záměrem
  • žádné významné změny však s dopadem na klinickou praxi nebyly zaznamenány.
  • www.farmakoterapie.cz/c4793/perspektivy-v-lecbe-maligniho-melanomu

Dehydroacetic acid

  • Inhibits acetoacetate's effects on V600E tumor growth.
  • Dehydroacetic acid is used in cosmetics and appears to have low toxicity,
    • But clinical studies would be needed to assess its anticancer properties, especially at the levels that could alter cell metabolism.
  • www.sciencedaily.com/releases/2017/01/170112141359.htm

(–)-Epigallocatechin gallate (EGCG)

  • Green tea derived from dried unfermented leaves of Camellia sinensis (family Theaceae)
  • Antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer-preventive activities
  • Major dry mass constituent is the family of catechins includes
    • (+)-gallocatechin,
    • (–)-epicatechin,
    • (–)-epigallocatechin (EGC),
    • (–)-epicatechin gallate (ECG)
    • (–)-epigallocatechin gallate (EGCG)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Several studies have been performed to determine the effect of these compounds on the growth and viability of melanoma cells (Valcic et al., 1996)
  • EGCG treatment of melanoma cell lines
    • Resulted in decreased cell proliferation
  • EGCG-induced cell cycle arrest and apoptosis of melanoma cells
    • Modulations in the cki-cyclin-cdk network and Bcl2 protein family
  • Similar EGCG concentration, normal melanocytes were not affected
  • EGC, ECG and EGCG on the viability, density and doubling time of cell lines derived from melanoma metastasized to lymph nodes or distant organs.
    • Cytotoxic effect and growth inhibition of all melanoma cell lines tested was most pronounced with EGCG
      • Anticancer action of the various catechins may vary with the type of malignancy (Ravindranath et al., 2009).
  • Efficacy of EGCG against colony formation, cell migration and invasion associated with
    • Decreased phosphorylation of focal adhesion kinase (FAK)
    • Downregulation of matrix metalloproteinases (MMPs)

EGCG + dacarbazine

Quercetin, apigenin, EGCG, resveratrol, and the anti-estrogen tamoxifen

  • EGCG, a potent inhibitor of MMP-2 and MMP-9
    • Selectively suppress the migration of tumor-associated endothelial cells
      • As well as endothelial progenitor cells
    • With no effect on normal endothelial cells
      • Antiangiogenic potential (Ohga et al., 2009)
  • Stromal cells are involved in key metastatic processes of melanoma and other solid tumors.
  • EGCG can modulate the behavior of stromal fibroblasts
    • Affecting their adhesion and migration through multiple mechanisms
  • Fibroblast adhesion to fibronectin and fibrinogen
    • Inhibited by EGCG through binding to these compounds
    • Mediated through its effect on integrin alpha2beta1
  • EGCG decreased the intracellular H2O2 levels
    • Altering the tonic balance required for cell adhesion to collagen (Ohga et al., 2009)
  • EGCG significantly upregulated the expression of
    • E-cadherin associated with decreased invasion and metastasis (Wu et al., 2008)
    • Enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in melanoma cells (Shen et al., 2009; Tanaka et al., 2010)
  • Inhibitory effect of EGCG on adhesion of melanoma cells to laminin
    • Included in the mechanism(s) of previously reported metastasis inhibition (Suzuki and Isemura, 2001)
  • 67-kDa laminin receptor (67LR) conferred EGCG responsiveness to tumor cells
  • Eukaryotic translation elongation factor 1A and 67LR that EGCG induced the dephosphorylation of myosin phosphatase
    • Targeting subunit 1 at the threonine residue
    • Activated myosin phosphatase
    • Resulting in growth inhibition of tumor cells (Umeda et al., 2008)
  • Concentration of EGCG required to elicit anticancer effects
    • Is much higher than the peak plasma concentration obtained after drinking an equivalent of two to three cups of green tea
    • Combination regimens have been tried in several in vitro and in vivo studies
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

All-trans-retinoic acid (ATRA) + EGCG

  • On subcutaneous tumor growth in mice inoculated with melanoma cells
  • Combined treatment significantly suppressed melanoma tumor growth in mice
  • Increased the expression of 67LR in the tumor tissue.
  • Attenuated 67LR expression in melanoma cells upon RNAi-mediated silencing of the retinoic acid receptor alpha
    • Further demonstrated that ATRA enhanced the antitumor effect of EGCG
      • Through upregulation of 67LR (Lee et al., 2010b)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

7-OMe

SAHA-suberoylanilidine hydroxamic acid Zolinza (vorinostat) + EGCG

  • An FDA-approved HDAC inhibitor
  • Combination treatment resulted in significantly greater inhibition of cell proliferation
    • Increased apoptosis
    • Associated with activation of p21(CIP1), p27(KIP1) and caspases –3, –7 and –9, and pro-apoptotic protein Bax
    • As well as downregulation of cdks –2 and –4, cyclin A, and antiapoptotic Bcl2 (Nihal et al., 2010)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

Immunomodulatory cytokine IFN-alpha2b + EGCG

  • Commonly used in melanoma treatment with marginal efficacy and high toxicity
  • Combination was more effective than either agent alone
  • Marked decrease in cell proliferation and colony formation ability, and induction of apoptosis.
  • This was accompanied by an increase in Fas protein levels
    • Fas-ligand-mediated apoptosis
    • A decrease in nuclear factor kappa B (NF?B)/p65 activity
  • Athymic nude mice implanted with melanoma tumors
    • Showed a decrease in tumor growth and protein levels of proliferation marker PCNA in the combination group
  • Signifying that EGCG could impart therapeutic advantage if used in conjunction with IFN (Nihal et al., 2009).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

DNA vaccination + EGCG

  • Found to be effective in inhibiting melanoma growth
  • Combination treatment led to an enhanced tumor-specific T-cell immune response
    • Resulting in a higher cure rate than either therapy alone
  • Combined DNA vaccination and oral EGCG treatment
    • Provided long-term antitumor protection in cured mice
    • Suggesting that combining immunotherapy with a tumor-killing cancer drug may be an effective anticancer strategy (Kang et al., 2007)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

EGCG with hinokitiol (beta-thujaplicin)

  • Synergistic activity on melanogenesis
  • EGCG in synergy with hinokitiol significantly inhibited melanin synthesis
  • Reduced protein levels of microphthalmia-associated transcription factor (MITF) and tyrosinase
    • The rate-limiting melanogenic enzyme (Kim et al., 2004).
  • EGCG may prevent UV-induced immunosuppression and subsequent photocarcinogenesis
  • IL-12 knockout mice
    • Topical treatment with EGCG prevented UV-induced suppression of contact hypersensitivity in wild-type mice
      • Had no effect in the knockout mice
  • Injection of anti-IL-12 monoclonal antibody to wild-type mice
    • Blocked the preventive effect of EGCG
      • Prevention of UV-induced immunosuppression by EGCG is mediated through IL-12-dependent DNA repair
  • EGCG-mediated repair of UV-induced DNA damage was more efficient in the skin of wild-type mice
    • Reduced number of cyclobutane pyrimidine dimer (CPD)-positive cells
    • Decreased migration of CPD-positive antigen-presenting cells from the skin to draining lymph nodes (Meeran et al., 2006)
  • EGCG failed to repair UV-induced CPDs in DNA repair-deficient cells from XPA patients
    • Involvement of nucleotide excision repair mechanism in EGCG-mediated DNA repair (Meeran et al., 2006)
  • no clinical trials underway to assess the efficacy of EGCG against melanoma
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

Exo-biopolymer from rice bran


Fisetin (3,7,3',4'-tetrahydroxyflavone)

  • Belongs to the flavonol subgroup of flavonoids
  • Strawberries, apples, persimmons and onions (Kimira et al., 1998)
  • Originally identified in a screen for compounds that could prevent oxidative stress-induced nerve cell death (Ishige et al., 2001)
  • Possessed neurotrophic activity
    • Promoting nerve cell differentiation via activation of the Ras-ERK cascade (Sagara et al., 2004)-
  • Oral administration of fisetin
    • Enhance learning and memory in mice (Maher et al., 2006)
  • Direct antioxidant
  • Increase the intracellular levels of glutathione
  • Anti-inflammatory activity
    • Inhibit the activity of 5-lipoxygenase in microglia cells
      • Reducing the production of lipid peroxides and their proinflammatory byproducts (Syed et al., 2008)
  • Possesses anticancer properties
  • Induced apoptosis in various cancer cell lines
    • Activation of the caspases
    • Inhibition of cdks (Syed et al., 2008)
    • Inhibition of uPA by fisetin in the advancing capillary vessels surrounding the tumor
      • May be responsible for reducing angiogenesis and consequently tumor growth (Jankun et al., 2006)
  • Treatment of human melanoma cells with fisetin
    • Resulted in decreased cell viability with G1-phase arrest
    • Disruption of Wnt/beta-catenin signaling
  • Decrease in the expression of Wnt protein and its co-receptors
  • Increase in expression of endogenous Wnt inhibitors Dickkopf and WIF-1 (Syed et al., 2011)
  • Increased cytosolic levels of Axin and beta-TrCP
  • Decreased phosphorylation of GSK3-beta
    • Correlated to decreased beta-catenin stabilization in fisetin-treated melanoma cells
  • Fisetin-mediated interference with the functional cooperation
    • Between beta-catenin and the transcription factor LEF/TCF-2
    • Resulted in down-regulation of positively regulated TCF targets such as c-myc, Brn-2 and MITF
  • Retention of MITF expression in human primary melanomas, including non-pigmented ones
    • Led to its use as a diagnostic tool in melanoma
  • Targeting MITF in combination with B-RAF or cdk inhibitors
    • May offer a rational therapeutic avenue into melanoma (Garraway et al., 2005)
  • Fisetin was able to override the proliferative effect of MITF
    • And induce growth repression in human melanoma cells
  • Intraperitoneal administration of fisetin to mice
    • Resulted in inhibition of human melanoma tumor development associated with a significant decrease in endogenous MITF protein levels (Syed et al., 2011)
  • Fisetin can be developed as an effective agent against melanoma due to its potential inhibitory effect on beta-catenin/MITF signaling.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

Garlic extract


Genistein (4'5,7-trihydroxyisoflavone)

  • Flavonoid present in human diet
  • Derived mainly from soybeans
  • Also found in other legumes, including peas, lentils and beans
  • Occurs as the glycoside genistin
  • Metabolized to the aglycone genistein in the lower gut
  • Genistein
    • Is partly absorbed without previous cleavage
    • Does not have to be hydrolyzed to become biologically active
  • Antioxidant, antimicrobial, phytoestrogenic, and tyrosine kinase inhibitor activities
  • Genistein protected against DNA damage induced by hydroxyl radicals, generated from UV photolysis of hydrogen peroxide.
  • Inhibition of topoisomerase II and tyrosine kinases
    • To suppress growth and increase melanin content in several different human melanoma cell lines (Kiguchi et al., 1990)
  • The up-regulation of the cyclin-dependent kinase inhibitor (cdki) p27(KIP1) by genistein
    • Inhibition of cyclin-dependent kinase (cdk)-2,
  • P21(CIP1) is dispensable for genistein-induced G2 arrest (Casagrande and Darbon, 2000)
  • Genistein-induced growth inhibition of melanoma cells might depend on cellular p53 content
  • High levels of p53 make melanoma cells resistant to the growth inhibitory action of genistein
  • Induction of differentiation of melanoma cells by genistein
    • Regulated by cellular p53
      • Cells lacking p53 responded readily to genistein-induced dendrite-like structure formation (Rauth et al., 1997)
  • Genistein-induced cellular differentiation occurs through stabilization of protein-linked DNA strand breakage (Constantinou and Huberman, 1995; Yan et al., 1999)
  • Correlation between the growth inhibitory activity of genistein and miR-27a has been reported.
    • Levels of miR-27a and its target gene ZBTB10
      • Were significantly altered in genistein-treated melanoma cells (Sun et al., 2009).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Genistein and daidzein
    • Another isoflavonoid present in dietary soybean
    • Differential effects on the viability of melanoma cells (Russo et al., 2006)
  • Genistein treatment resulted in arrest of melanoma cells in the G2 phase of the cell cycle
  • Daidzein, which lacks a hydroxyl group
    • Induced accumulation of cells in the G1 phase
  • Genistein exerted this effect by impairing the Cdc25C-dependent tyrosine dephosphorylation of cdk-1
    • Activating the checkpoint kinase (Chk)-2 (Darbon et al., 2000)
  • Genistein treatment induced melanoma cells to acquire dendrite-like structures
    • Increased the production of melanin
  • Daidzein only retarded the growth of these cells
    • Failed to induce differentiation
    • Genistein and daidzein can inhibit certain malignant phenotypes of melanoma via different mechanisms (Wang et al., 2002).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Dietary supplementation with genistein and daidzein
    • Reduced tumor size and number as well as lung metastasis in mice injected with melanoma cells (Li et al., 1999).
  • One study showed that growth of solid tumors
    • Was inhibited by 50% when mice were fed genistein for 1 week before and after inoculation with melanoma cells
  • Plasma genistein concentrations at the time of tumor removal
    • Were similar to levels reported in humans consuming diets high in soybeans or soybean products (Record et al., 1997)
  • Administration of genistein intraperitoneally
    • Reduced tumor-induced angiogenesis in syngeneic mice implanted with melanoma cells (Farina et al., 2006)
  • Genistein inhibited nodule formation in the lungs of tumor-bearing mice
    • Reduced the lung collagen hydroxyproline content and serum sialic acid level, a marker of metastasis.
  • In contrast, the same study found no significant effect on the reduction of lung metastasis with daidzein (Menon et al., 1998).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Impaired extracellular signaling by genistein
    • Might prevent cancer cells from invading or establishing metastasis through
      • Suppression of adhesion-induced protein tyrosine phosphorylation (Yan and Han, 1997)
  • Genistein at physiologic concentrations
    • Enhanced cisplatin-induced inhibition of cell growth and apoptosis in human melanoma cell lines (Tamura et al., 2003)
  • Genistein, alone or combined with cyclophosphamide therapy
    • Results indicated a higher antiangiogenic rather than cytostatic effect of genistein in the mouse tumor model (Wietrzyk et al., 2001)
  • Antitumor effect of genistein, alone or in combination with cyclophosphamide
    • In mice bearing transplantable subcutaneously growing tumors, by estimating the number of lung colonies and primary tumor recurrence
    • A reduced number of lung colonies in mice bearing lung tumor implants were observed in the genistein-treated group
    • More pronounced with the combination
    • no lung metastases in the control mice bearing the melanoma tumor were observed
    • Primary tumor recurrence was highest in the untreated group and lowest in the group treated with genistein alone (Wietrzyk et al., 2000).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Long-term psoralen plus ultraviolet A radiation (PUVA) therapy
    • Associated with an increased risk of squamous cell carcinoma and malignant melanoma (Shyong et al., 2002)
  • Application of genistein significantly decreased PUVA-induced skin thickening, erythema, ulceration and epidermal inflammation in mice
    • Was associated with inhibition of
      • Poly(ADP)ribose polymerase (PARP) cleavage
      • Caspase-3 activation
      • A decrease in proliferating cell nuclear antigen (PCNA)-positive cells in the suprabasal layers of the epidermis (Shyong et al., 2002)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Genistein modulates immune responses
  • Increases host resistance to melanoma tumors in mice
    • Not due to a direct effect of serum levels of genistein and/or its metabolites on cellular proliferation
    • But through an increase in cytotoxic T-cell activity
  • IL-2-stimulated natural killer cell activity is enhanced by genistein (Guo et al., 2001)
  • Genistein exhibited inhibitory effects against IL-5 and IL-3 bioactivities
    • But did not inhibit GM-CSF and IL-6 bioactivities (Yun et al., 2000).

A phase II clinical trial

  • Will determine the effect of genistein together with IL-2 in patients with metastatic melanoma or renal clear cell carcinoma.
  • Genistein may stop the growth of tumor cells through
    • Antiangiogenic effect,
    • IL-2 may stimulate the immune system to kill tumor cells
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717
  • Also non-nucleoside HIV-1 RT inhibitors
    • Nevirapine and Efavirenz were tested against HERV-K(HML2) expression
      • Reducing proliferation and promoting apoptosis in melanoma cells with induced stemness features (Argaw-Denboba et al., 2017).
  • www.frontiersin.org/articles/10.3389/fmicb.2018.00462/full


Hesperitin


Imiquimod cream


Immune checkpoint inhibitors

Immunotherapy

Imunoterapie zaměřená na protein PD-1

  • Prevalence metastazujícího melanomu rok od roku roste
  • Pacientům výrazně prodloužila život.
  • „Ze skupiny pacientů, jimž byla nasazena imunologická léčba a přežili jeden až tři roky, prakticky nikdo neumírá.
  • Nemocní se nemohou považovat za vyléčené, ale dostávají se z akutního do tzv. chronického stadia, které známe například ve spojitosti s infekcí HIV.
  • V dnešní době jsme právě díky imunoterapii schopni protáhnout dobu spolužití s nádorovými buňkami,“ uvedl přednosta Dermatovenerologické kliniky 3. LF UK a FNKV v Praze prof. MUDr. Petr Arenberger, DrSc.
  • Odkázal i na závěry studií (KEYNOTE), podle nichž je 91 % pacientů po dvou letech léčby pembrolizumabem bez známek progrese.

Látky, které potlačují novotvorbu cév

Potraviny


Zelený, bílý čaj, oolong, černý čaj

Cranberries

čokoláda, kakao

červené víno

Guáva

Fazole - fava

Brambory

Jahody

Ostružiny

Kivi

Třešně

Hrušky

Broskve

Jablka (slupka, jádřinec)

Avokáda

Pekanové ořechy

Pistácie

Lískové oříšky

Mandle

šalotka

Cibule

Bobulovité ovoce

Hovězí chrupavka a maso

Káva

Kakao

Mléko

Skopové maso a jehněčí

Jablka

Artičoky

Mrkve

Lilek

Hroznové víno - semínka, slupičky

švestky

Brambory

Listy tabáku

Rajčata

Med

Propolis

Dýně a tykve

Zázvor

Borůvky

Zelenopyskaté mušle

Soja, tofu, tempeh, sojova omačka

Pistacie

Víno Cabernet Sauvignon

Brusinky

Hroznové víno Concord

Granatové jablko (slupičky a pecičky,....barvivo)

Lilek (slupka)

černý ribíz

Citrusy

Zázvor

Olivový olej (asi obojetný)

Byliny


Fialky

Rajská švestka, abajeru nebo icaco

Zimolez

Gumojilm jilmový

Betel

Lopuch

Právenka latnatá

Pelyněk roční

Barvínkovec růžový

Dřišťál

Koptis čínský

Štětinec laločnatý

Ostropestřec mariánský

Semínka vinné révy / vína - olej, ocet, extrakt

Lékořice

Boswelie

Meduňka lékařská

Ibišek súdánský

Magnolie

Třezalka tečkovaná

Heřmánek

Bazalka

Křídlatka japonská

Rozmarýn

Šišák bajkalský

Vrba

Phytolacca americana (American pokeweed),

Syzygium spp,

Olea europaea (leaves, fruit),

Rosa woodsii (leaves),

Prosopis glandulosa (leaves and twigs),

Phoradendron juniperinum (whole plant),

Syzygium claviflorum (leaves),

Hyptis capitata (whole plant),

Mirabilis jalapa

Ternstroemia gymnanthera (aerial part)

Java apple (Syzygium samarangense) and rose apples

Boesenbergia rotunda

Doplňky


(-)-epigallocatechin-3-gallate

Propolis

Resveratrol

Vitamins A, C, E; Se, Zn; carotenoids, flavonoids,

Omega-3 nenasycené mastné kyseliny (EPA, DHA)

Bromelain

Quercetin

Ganoderma lucidum

Genistein

Hesperetin

Lykopen

Pleurotus tuber-regium

Selen

žraločí chrupavka

Boswelia

Sulforafan

Theaflavin

Léky


Aspirin

Nesteroidní antirevmatika - inhibitory COX2

Interferon beta


Inhibitory laktát dehydrogenázy

  • Dohledat

Inhibitory reverzní transkriptázy

  • By mohly mít zajímavý efekt u metastatického melanomu:
  • Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas
    • "retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma."
  • biosignaling.biomedcentral.com/articles/10.1186/s12964-020-00633-7
  • Melanoma cells can produce retrovirus-like particles that exhibit RT activity and comprise mature GAG and ENV proteins.
    • "In immunocompetent mice, the inhibition of murine melanoma-associated retrovirus (MelARV) resulted in a reduction of melanoma aggressiveness and rejection of melanoma cells inoculated in nude mice, suggesting that MelARV acts to evade the immune system."
    • "Blockage of HERV-K by RNA interference and monoclonal antibodies in melanoma cells, resulting in a marked reduction in colonic growth of melanoma cells in vitro.52 "
    • "The down-regulation of the HERV-K reverse transcriptase by RNA interference or pharmacological inhibitors resulted in a lower mitotic rate and induced morphological differentiation,52–54 and slowed down melanoma growth and formation of metastasis in vivo."
  • www.dovepress.com/k-type-human-endogenous-retroviral-elements-in-human-melanoma-peer-reviewed-fulltext-article-AGG
  • ::4 October 2014 Volume 2014:4 Pages 153—159::
  • Podobných prací je ještě celá řada, ale nejedná se o klinické studie na lidech (zatím jsem nenašla).
  • Riziko žaludeční nevolnosti, požadavek dobré renální funkce vstupně, ale nějaká šance na zpomalení choroby snad možná je.

Iodine-125 plaque radiotherapy

  • Regression of posterior uveal melanoma following iodine-125 plaque radiotherapy based on pre-treatment tumor apical height

Ipilimumab (Yervoy)

  • Ipilimumabem navozená blokáda CTLA-4 v léčbě metastazujícího melanomu – dlouhodobé výsledky 177 pacientů
  • Ipilimumab je plně humánní IgG1 monoklonální protilátka
  • Produkovaná rekombinantní technologií DNA na ovariálních buňkách čínského křečka
  • Navození blokády receptoru T-lymfocytů označovaného jako CTLA-4 (cytotoxický T-lymfocytární antigen- 4)
    • Negativní regulátor aktivace těchto buněk, jejich proliferace a konečně i infiltrace do nádorových buněk
  • V nedávné době byl ipilimumab schválen pro léčbu pacientů s maligním melanomem.
  • Ve studiích I. a II. fáze se hodnotila jeho účinnost při současném podání s vysokými dávkami interleukinu-2 (IL-2).
  • V roce 2010 byly prezentovány výsledky studie III. fáze (n = 676)
    • Patrný příznivý účinek ipilimumabu ve srovnání s aplikací peptidové vakcíny gp100 v monoterapii či ve vzájemné kombinaci.
  • Ve třech klinických studiích bylo léčeno ipilimumabem 177 pacientů, u kterých bylo možno hodnotit délku odpovědi na léčbu.
  • www.farmakoterapie.cz/c3397/ipilimumabem-navozena-blokada-ctla-4-v-lecbe-metastazujiciho-melanomu-dlouhodobe-vysledky-177-pacientu
  • Imunoterapie metastazujícího melanomu je zaměřena zejména na receptory CTLA-4 a PD-1, jejichž zablokování zvyšuje aktivitu cytotoxických T-lymfocytů a protinádorovou imunitu.
  • Nejúčinnější inhibitor CTLA-4 ipilimumab byl na základě výsledků studie CA 184-002 schválen FDA i EMA pro léčbu metastazujícího melanomu.
  • Jedná se o první lék, který dokázal statisticky významně prodloužit celkové přežití nemocných.
  • Léčebné odpovědi dosahuje pouze 20–30 %, ale jsou dlouhodobé. (!!!)
  • www.farmakoterapie.cz/c3642/pokroky-v-lecbe-metastazujiciho-melanomu

Isoprinosine

  • Dohledat

Isothiocyanates derived from wasabi


Itraconazole

  • Inhibits tumor cell growth, cell proliferation, and colony formation in melanoma
  • Downregulation of the expression of Gli-1, Gli-2, Wnt3A, b-catenin, and cyclin D1
    • Obstruction of the Hedgehog and WNT signaling pathway
  • Itraconazole also inhibits the phosphorylation of p70S6K, 4E-BP1, and AKT
    • Suppresses the PI3K/mTOR signaling pathway
  • In pancreatic and ovarian cancers, Itraconazole, in combination with chemotherapeutic drugs
    • Significantly enhances the overall survival of patients
  • Inhibition of angiogenesis by its triazole unit
  • Induces cell cycle arrest,
  • Blocks the endothelial growth factor
    • Leads to an inhibition of angiogenesis
  • In clinical phase I and II trials against different cancers (i.e., prostate, lung, and Esophageal)
  • www.mdpi.com/2072-6694/13/13/3193/htm

Ivermectin

  • In murine multidrug-resistant (MDR)-P388 and human MDR-CEM leukemia cells
    • Was a substrate and inhibitor of P-glycoprotein-mediated multidrug resistance in cancer
  • Ivermectin, at doses of 3–5 mg/kg
    • Suppress the growth of human melanoma
      • And number of other cancer xenografts in mice without adverse effects
  • Ivermectin exhibits a high degree of similarity with salinomycin
    • Preferentially inhibited the CSC subpopulation in a breast cancer model.
  • doi.org/10.3892/mmr.2017.8231

Kombinace

Inhibitor BRAF (vemurafenib) + inhibitor MEK (cobimetinib)

  • Zlepšuje přežití bez progrese (PFS) ve srovnání s monoterapií inhibitorem BRAF u pacientů s mutací BRAF V600 (studie CoBRIM)

Dabrafenib + trametinib

  • U pacientů s mutací BRAF V600E/K - zlepšení

Encorafenib + binimetinibu

  • Zlepšení u nemocných s maligním melanomem s mutací BRAF V600

Nivolumab + ipilimumab

  • U nemocných s pokročilým melanomem i kombinační imunoterapie
    • Více než zdvojnásobila medián PFS oproti ipilimumabu samotnému ve studii CheckMate 067
  • Samotný nivolumab se ukázal jako účinný u pacientů s expresí ligandu PD-L1 (programmed cell death ligand-1).
  • Výsledky této studie byly prezentovány na každoročním setkání ASCO 2015 jako první studie III. fáze, která hodnotila kombinaci anti-P-D1 a anti-CTLA-4 léků.
  • Tak tahle kombinace je zatím můj vyčtený favorit...

Kurkumin

  • Liposolubilní
  • Curcumin (diferuloyl methane)
    • Major pigment from the rhizome of Curcuma longa L.
  • Widely studied for its tumor-inhibiting properties
  • Attempt to repair photodamaged skin as a means of preventing degeneration into solar-induced skin cancers.
  • Utility in photoaging skin and photocarcinogenesis
  • curcumin induced melanoma cells to undergo apoptosis and cell cycle arrest
  • Downregulation of
    • INOS
    • DNA-dependent protein kinase catalytic subunit expression
  • Upregulation of
    • P53,
    • P21(CIP1),
    • P27(KIP1)
    • Chk-2 (Zheng et al., 2004)
  • curcumin induced apoptosis in melanoma cells through
    • Fas receptor/caspase-8 pathway independent of p53
    • Suppressed the apoptotic inhibitor, XIAP
    • Blocked the NF?B cell survival pathway
      • Resulting in decreased expression of NF?B-target genes COX-2 and cyclin D1 (Marin et al., 2007; Bush et al., 2001)
  • Induced ER stress in melanoma cells through
    • Inhibition of proteasomal activity
    • Accumulation of cytosolic calcium
      • By inhibiting the Ca2+-adenosine triphosphatase (ATP) pump
        • Resulting in activation of caspases,
        • P23 cleavage and downregulation of the antiapoptotic Mcl-1 protein (Bakhshi et al., 2008)
  • Gene silencing of ATP-binding cassette transporter ABCA1 by siRNA
    • Sensitizes melanoma cells to the apoptotic effect of curcumin
      • Through reduced basal levels of active NF?B (Bachmeier et al., 2009)
  • C6 ceramide
    • Sensitized melanoma cells to curcumin-induced cell death and apoptosis
      • Via augmentation of the intrinsic apoptotic pathway (Yu et al., 2010)
  • curcumin + tamoxifen
    • Induced apoptosis and autophagy in melanoma cells
    • Non-cancerous cells were unaffected by the combination treatment (Chatterjee and Pandey, 2011)
  • Curcumin-induced anti-proliferative and proapoptotic effects
    • Independent of the B-Raf/ERK MAPK and the AKT pathway (Siwak et al., 2005)
  • curcumin reportedly inhibited the ability of IFN-alpha, IFN-gamma, and IL-2 to phosphorylate STAT1 and STAT5 proteins (Bill et al., 2009)
    • curcumin may adversely affect the responsiveness of immune effector cells to clinically relevant cytokines with antitumor properties (Siwak et al., 2005).
  • Suppress melanogenesis in stimulated melanoma cells
    • Through downregulation of melanogenesis-related proteins such as
      • MITF,
      • Tyrosinase
      • Tyrosinase-related proteins 1 and 2 (Lee et al., 2010a)
  • Antimetastatic activity of curcumin
    • Modulation of integrin receptors,
    • Collagenase activity
    • E-cadherin
  • curcumin-treated cells
    • Diminished binding to extracellular matrix proteins such as
      • Fibronectin, vitronectin and collagen IV
    • Decreased expression of
      • Alpha5beta1 and alpha5beta3 integrin receptors
  • Inhibited MMP-2, FAK and collagenase activity
  • Enhanced the expression of antimetastatic proteins including
    • Tissue inhibitor metalloproteinase-2
    • Nonmetastatic gene 23
    • E-cadherin (Banerji et al., 2004; Ray et al., 2003).
  • curcumin-related compounds have been synthesized and tested

Compound alpha,beta-unsaturated ketone D6

  • Was more effective in inhibiting melanoma growth when compared to curcumin (Pisano et al., 2010)

Synthetic curcuminoid derivatives

  • Were further analyzed in in vivo studies for their role in inhibition of tumor-specific angiogenesis.

Tetrahydrocurcumin, salicyl curcumin and curcumin III

  • Intraperitoneal administration
  • Reduced the number of tumor-directed capillaries induced by injecting mice with melanoma cells
  • Treatment reduced serum NO as well as tumor-necrosis factor (TNF)-alpha levels in these animals
    • V.s. via decreased production by the activated macrophages (Leyon and Kuttan, 2003)

Curcumin analog FLLL32

  • Developed to improve STAT3-specific inhibitors for melanoma therapy
  • FLLL32 induced caspase-dependent apoptosis in melanoma cells
    • Via reduced STAT3 phosphorylation at the tyrosine residue
    • But retained the cellular response to cytokines with antitumor activity
  • FLLL32 did not reduce the function or viability of immune cells from normal donors
  • Peripheral blood mononuclear cells
    • FLLL32 inhibited IL-6-induced STAT3 phosphorylation
    • But did not reduce signaling in response to immunostimulatory cytokines such as IFN-c and IL-2 (Bill et al., 2009)
  • Potential chemotherapeutic agent

Amphiphilic block copolymer micelles of poly(ethylene oxide)-b-poly(epsilon-caprolactone)

  • As vehicles for solubilization, stabilization and controlled delivery of curcumin (Ma et al., 2008).
  • Curcumin was shown to be cytotoxic to melanoma cells resistant to doxorubicin
  • Animals on curcumin + immune preparation of soluble protein
    • Exhibited an enhancement of their humoral immune response
      • Subsequent increase in the median survival time (Odot et al., 2004)
  • curcumin suppressed
    • Osteopontin-induced cell migration,
    • Tumor growth
    • NFjB-mediated MMP-2 activation (Philip and Kundu, 2003)
  • Phosphatase of regenerating liver-3 (PRL-3)
    • Suggested as a potential target for anticancer drugs
      • Involvement in tumor metastasis
  • In a spontaneous metastatic tumor model, curcumin selectively downregulated the expression of PRL-3 but not PRL-1 or -2
    • In a p53-independent manner
  • Curcumin inhibited phosphorylation of Src kinase and STAT3
    • Partly through PRL-3 downregulation
    • Prevented melanoma cells from invading the draining lymph nodes (Wang et al., 2009)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

L-fucose

  • Could inhibit melanoma tumor metastasis
  • Tumors were affected, also their microenvironment
  • L-fucose, provide crucial tags on cell-surface proteins
    • Signal inflammation and help direct cell migration
  • Changes in the amount of L-fucose on cells are associated with breast and stomach cancers.
  • Genes found to be regulated by ATF2 was fucokinase (FUK)
    • Controls the ability of cells to process the dietary sugar, L-fucose, into a form that is useable for the modification (fucosylation) of proteins, many of which are on the cell surface
  • Reduced fucosylation in metastatic melanomas
  • Better prognosis for primary melanomas with increased fucosylation
  • Absence of L-fucose on melanoma cells makes them less sticky and more mobile in the body
  • In mice with melanoma
    • Increase fucosylation either by adding the sugar to their drinking water or by genetic manipulation.
    • Both methods inhibited the growth and metastasis of the tumors.
  • Addition of dietary sugar may help fight melanoma by boosting numbers of helpful immune cells
  • www.sciencedaily.com/releases/2015/12/151208150954.htm
  • DOHLEDAT

LDH-A inhibitory

  • Zejména u melanomu a glioblastomu

Levamisole

  • Potent activity against lung cancer, melanoma, and myeloma, in vivo and in vitro
  • Inhibits myeloma cells by inducing the loss of CD138
    • A transmembrane heparin sulfate glycoprotein enhanced in malignant cells and by increasing IL-6 secretion
  • In lung cancer cells, it inhibits cJNK phosphorylation
    • Induces cell cycle arrest and tumor necrosis factor-related apoptosis
  • Many trials are ongoing to test its efficacy when combined with other standard chemotherapeutic agents such as
    • 5-fluorouracil to treat colon cancer (NCT00002593, NCT00425152, NCT00002551, NCT00309530, NCT00003063)
  • www.mdpi.com/2072-6694/13/13/3193/htm

Lopinavir

Lunasin

  • Melanoma is initiated and maintained by a small population of malignant cells called cancer-initiating cells (CICs)
    • Stem-cell-like properties
    • CICs have a distinct biology when compared to that of the bulk tumor cells
    • Resistant to chemotherapies and radiation
  • Lunasin, a bioactive peptide present in soybean
  • Chemopreventive activity
  • Chemotherapeutic activity against multiple cancer types

In vitro studies using human melanoma cell lines

  • Lunasin treatment
    • Decreased the size of a subpopulation of melanoma cells expressing the surrogate CIC marker
  • Aldehyde Dehydrogenase
    • Concomitant with a reduction in the ability to form colonies in soft agar assays

Mouse xenografts

  • Reduced tumor growth
  • Lunasin inhibited colony formation by isolated melanoma CICs in soft agar
  • Reduced oncosphere formation in vitro
  • Inhibited tumor growth in mouse xenografts
  • Lunasin treatment of isolated melanoma CICs induced expression of the melanocyte-associated differentiation markers
    • Tyrosinase
    • Microphthalmia-associated Transcription Factor
      • Concomitant with reduced expression of the stemness factor NANOG
  • Lunasin has significant therapeutic activity against melanoma
  • Lunasin may represent a novel therapeutic option for both chemoresistant and advanced metastatic melanoma management.
  • Melanoma cells with stem-cell-like plasticity
    • Overexpressed CD20, CD133
    • Characteristics of stem cells
    • Enhanced ability to form palpable tumors in immunodeficient mice
    • ABCB5
    • CD271
      • Potential melanoma CIC biomarkers
  • Melanoma cells expressing Aldehyde Dehydrogenase (ALDH)
    • Stem-cell-like properties
    • Enhanced in vivo tumorigenic capacity
    • ALDH as a CIC marker
    • ALDH1 expression correlates with poor prognosis in breast, ovarian, lung cancers
    • Critical in the development and differentiation of hematopoietic stem cells
      • Modulating retinoid signaling through the conversion of vitamin A (retinol) to retinoic acid
        • Ligand for downstream nuclear receptors retinoic acid receptor (RAR) and retinoid X receptor (RXR)
  • Lunasin
    • Amino acid peptide component of the 2S albumin protein
  • Robust chemopreventive and chemotherapeutic activities
  • Decreasing proliferation of non-small cell lung cancer (NSCLC) cells
    • Suppressing integrin signaling through alphavbeta3
    • Lunasin is internalized via alphavbeta3 integrin
    • Expression of alphavbeta3 integrins are lower in non-transformed epithelial cells
    • Expression levels of alphavbeta3 correlate with the metastatic potential and the conversion of melanoma neoplasms to a metastatic phenotype
  • Lunasin specifically targets ALDHhigh CICs in human melanoma cell lines
  • Lunasin treatment decreases the expression of surrogate CIC markers in vitro
    • Affects their in vivo tumorigenicity
  • Reduces formation of CIC-enriched melanoma oncospheres
  • Induces expression of melanocyte-associated differentiation markers
  • Suppressing a stem-cell-associated factor

Tumor xenografts by subcutaneous (s.c.) implantation of A375 cells in athymic nude mice

  • Subsequent daily intraperitoneal (i.p.) injections of Lunasin (30 mg/kg body weight)
  • Significant reduction in the tumor growth rate was observed in the Lunasin-treated mice
  • Mice in the Lunasin-treated group displayed tumors at this time that were significantly smaller (do 50 mm3)
    • Difficult to measure due to their small size and lack of depth
  • Mice treated with Lunasin over a 34 day period exhibited significant reductions in tumor volume (55%) and total tumor mass (46%)
    • Compared to those measured in the vehicle-treated mice
  • Lunasin was biologically active in vivo in this mouse model.
  • www.oncotarget.com/article/11554/text/

Lupeol

  • Triterpene widely distributed in various plant families
  • Mango pulp, carrot root, cucumber, soybean and melon seeds
    • Rich sources of lupeol
  • Earlier studies showed that lupeol present in alcoholic extracts of Taraxacum plants
    • Inhibited cell growth and induced melanogenesis in melanoma cells (Hata et al., 2000)
  • Several lupane triterpenes promote melano-genesis
    • A hallmark of melanoma cell differentiation
  • Keto function at C-3 of the lupane skeleton
    • Role in the melanogenic activity of lupane triterpenes
  • Carbonyl group at C-17 is essential for their apoptosis-inducing activity against human cancer cells
    • Via inhibition of topoisomerase I (Hata et al., 2006)
  • CAMP-elevating agents including enhance lupeol-induced differentiation
    • Alpha-melanocyte stimulating hormone
    • Forskolin
    • Dibutyryl cAMP
  • Lupeol-induced melanoma cell differentiation
    • Occurred through activation of p38 MAPK
    • Structural differences at C-3 of lupane triterpenes
      • Played an important role in the activation of p38 MAPK (Hata et al., 2003)
  • Melanoma cell differentiation induced by lupeol
    • Morphological and functional
  • Lupeol attenuates actin stress fiber assembly in melanoma cells
    • Resulting in dendritic formation in the cells
    • Followed by increased expression of tyrosinase, MITF, Rab27a and myosin-Va proteins required for melanosome transport (Ogiwara and Hata, 2009).
  • Lupeol suppresses the migration of malignant melanoma cells
    • Through disassembly of the actin cytoskeleton (Hata et al., 2005).
  • Lupeol inhibited the growth of highly aggressive human metastatic melanoma cells in vitro and in vivo through
    • Induction of apoptosis
    • Exerted only a marginal effect on normal human melanocytes
  • Lupeol-induced apoptosis
    • Accompanied by downregulation of Bcl2
    • Upregulation of Bax
    • Activation of caspase-3
    • Induction of PARP cleavage
  • Cell cycle arrest was associated with
    • Decreased expression of cyclin D1, cyclin D2 and cdk-2
    • Increased expression of p21(CIP1) proteins
  • Animal studies showed that lupeol significantly reduced melanoma tumor growth
    • Modulated the expression of
      • Proliferation markers PCNA
      • Ki-67,
      • Apoptotic markers,
      • Cell cycle regulatory molecules in tumor xenografts (Saleem et al., 2008)
  • Lupeol specifically targeted melanoma cells that harbored the
    • Constitutive Wnt/beta-catenin signaling pathway
    • Growth inhibition correlated with
      • Decrease in the expression of Wnt target genes c-myc, cyclin D1, invasion marker osteopontin (Tarapore et al., 2010)
  • Restricted the translocation of beta-catenin from the cytoplasm to the nucleus
  • Decreased the growth of melanoma cells with constitutive Wnt/beta-catenin signaling implanted in athymic nude mice
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717

N- hydroxyindole-based inhibitors of LDH-A (NHIs)

NY-ESO-1

  • Vysoce imunogenní antigen vyskytující se u řady maligních onemocnění, což jej do jisté míry předurčuje k tomu, aby se stal vhodnou cílovou strukturou pro vakcinaci proti nádorovému bujení.
  • Nedávno byla vyvinuta vakcína složená z rekombinantního NY-ESO-1 proteinu doplněná adjuvanciem ISCOMATRIX
    • Podání je provázeno výraznou humorální a T-buňkami zprostředkovanou buněčnou odpovědí
      • Lze proto předpokládat, že její podání může omezit výskyt relapsů u pacientů se zcela resekovaným melanomem.
  • Nově však bylo zjištěno, že ačkoliv je provedení vakcinace doprovázeno vzestupem titru protilátek, responzivita ve smyslu ovlivnění pozdního typu hypersenzitivity zůstává snížená.

Naringenin


Nelfinavir

  • HIV-1 protease inhibitor
  • Potent suppressor of PAX3 and MITF expression
  • Nelfinavir sensitizes BRAF, NRAS and PTEN mutant melanoma cells to MAKP inhibitors

Nivolumab


Oncolytic virus therapy

Pembrolizumab

  • Humanizovaná IgG4 monoklonální protilátka s vysokou afinitou k PD-1 receptoru exprimovanému na povrchu T-buněk.
  • Klinický přínos pembrolizumabu byl prokázán ve studiích KEYNOTE 001, 002 a 006
  • Pro léčbu dospělých s metastazujícím melanomem byla doporučena dávka 2 mg/kg každé 3 týdny
  • Nejčastějšími nežádoucími účinky pembrolizumabu jsou únava, svědění kůže, vyrážka, průjmy, endokrinní toxicita, hepatotoxicita a pneumonitida.
  • Pembrolizumab významně prodlužuje přežití do progrese i celkové přežití pacientů s metastazujícím melanomem a představuje pro tyto nemocné novou významnou léčebnou možnost.
  • www.farmakoterapie.cz/c4956/pembrolizumab-v-lecbe-metastazujiciho-melanomu

Pentostatin (2'-deoxycoformycin)

  • Zvýší antinádorový účinek cordicepsu
  • Single-agent pentostatin in intravenous doses of 4 to 5 mg/m2

Perillyl alcohol

  • A monoterpene isolated from the essential oils of
    • Lavendin,
    • Peppermint
    • And several other plants
  • Inhibit the growth of melanoma cells through
    • Modulation of small G-protein activity (Tatman and Mo, 2002)
  • Only a limited number of studies have examined the efficacy of this compound in melanoma

TPras transgenic mice

  • Topical application of perillyl alcohol delayed the appearance of melanoma tumors (Lluria-Prevatt et al., 2002)

Double-blind, randomized, phase II trial of topical perillyl alcohol in individuals with sun-damaged skin


Quercetin

Resveratrol (trans-3,5,4'-trihydroxystilbene)

  • First isolated in 1940
    • Constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes)
  • Various plants, including
    • Grapes, berries and peanuts
  • Cardioprotective effects,
  • Anticancer properties
  • Suppress proliferation of a wide variety of tumor cells
  • resveratrol induced cell-cycle disruption and apoptosis in chemoresistant melanoma cells (Gatouillat et al., 2010)
  • resveratrol-mediated apoptosis was significantly marked in melanoma cells
    • When associated with induction of ERK1/2 mitogen-activated kinase (MAPK) phosphorylation (Niles et al., 2003)
  • Upregulation of quinone reductase 2 and the p53 tumor suppressor gene (Hsieh et al., 2005)
  • resveratrol inhibits anchorage-independent growth through
    • Alterations in activated activator protein-1 (AP-1) transcription signaling
  • Reduces intracellular reactive oxygen species levels
  • It does not, even at high doses, cause apoptosis or cell cycle arrest in melanoma cells.
  • Number and position of hydroxy substituents seemed to play an important role in the inhibitory effects of stilbenes
  • Resveratrol and the structurally related molecule 4-hydroxystilbene induced
    • Growth inhibition, apoptosis,
    • S-phase arrest,
    • Upregulation of cyclins A, E and B1 in melanoma cells
    • Presence of two extra hydroxyl groups in reseveratrol
      • Diminished its efficiency to inhibit cell growth and arrest cell cycle in the S-phase with respect to 4-hydroxystilbene (Larrosa et al., 2003).
  • Depigmenting effect of oxyresveratrol
    • Reversible inhibition of tyrosinase activity rather than suppression of the expression and synthesis of the enzyme (Kim et al., 2002)
  • The methylated analogs of resveratrol
    • Possess significantly more antiproliferative activity than the parent compound (Cardile et al., 2007)

Piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene)

4'-resveratrol esters

Acetate and the palmitate analogs

Hexahydroxystilbene (M8)

  • Inhibited tumor as well as metastasis growth of human melanoma in two different animal models
  • Alone and in combination with dacarbazine (Szekeres et al., 2010).
  • Resveratrol potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation.
  • resveratrol sensitized melanoma cells for TRAIL-induced apoptosis
    • P53-independent induction of p21-mediated cell cycle arrest
      • Associated with survivin depletion (Fulda and Debatin, 2004)
  • Upregulation of transcription factors STAT3 and NFjB
    • Control the expression of antiapoptotic genes including cFLIP and Bcl-xL
      • Contribute to TRAIL-resistance in melanoma cells
  • resveratrol decreased STAT3 and NF?B activation
    • Activating the JNK/cJun pathway
      • Suppressed expression of cFLIP and Bcl-xL proteins
        • Increased sensitivity to exogenous TRAIL in DR5-positive melanomas
  • Initial increase in the surface expression of DR5 receptor
    • By either gamma-irradiation or arsenite
      • Subsequent downregulation of antiapoptotic cFLIP and Bcl-xL by treatment with resveratrol
        • Has been proposed as an effective approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas (Ivanov et al., 2008).
Takže nabaštit se rýže id. neloupané a potom si dát resveratrol... (?)
  • Resveratrol also upregulated TRAIL promoter activity
    • Induced TRAIL surface expression in some melanoma cell lines
      • Resulting in rapid development of apoptosis
  • Melanoma lines exhibiting suppressed translocation of TRAIL to the cell surface
    • A necrotic mechanism of cell death was primarily involved in radiation response
  • Surface expression of TRAIL induced by resveratrol
    • Appears to be a decisive event
      • Determines an apoptotic versus a necrotic response of melanoma cells to sequential treatment (Johnson et al., 2008).
  • Increased nuclear localization of apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ref-1)
    • A multifunctional protein involved in DNA repair
    • Redox regulation of many transcription factors
      • Present in nevi and malignant melanoma biopsies
  • In vitro studies have shown that Ref-1 overexpression
    • Protected melanoma cells from cisplatin- or H2O2-induced apoptosis
    • Associated with increased NFkappaB transcriptional activities
  • Virtual screening has shown that resveratrol docked into a druggable pocket of the Ref-1 protein
    • Inhibited Ref-1-activated AP-1 DNA-binding activities as well as Ref-1 endonuclease activities
    • Rendered melanoma cells more sensitive to dacarbazine treatment (Yang et al., 2005)
  • nitric oxide (NO) initiates progression of human melanoma
    • Via a feedback loop mediated by Ref-1 that is inhibited by resveratrol.
  • Significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels
    • Were observed after exposure to resveratrol (Yang et al., 2008).
  • Treatment with resveratrol markedly impaired proliferation of both temozolomide-sensitive and temozolomide-resistant melanoma cell lines (Fuggetta et al., 2004).
  • Resveratrol, at subtoxic doses,
  • resveratrol inhibited tumor growth and prolonged survival, supporting a potential use of resveratrol alone or in combination with other chemotherapeutic agents in the management of chemoresistant tumors (Gatouillat et al., 2010).

Trans isomer of resveratrol

  • Was found to be significantly more potent than the cis isoform when compared
    • Effect on the angiogenic process and endothelial alpha5beta3 function
  • Cell culture studies
    • Trans form inhibited endothelial cell proliferation
    • Prevented endothelial cell sprouting in fibrin gel, invasion in collagen gel, and morphogenesis in matrigel.
  • In animal studies
    • Trans-resveratrol inhibited murine melanoma tumor growth and neovascularization (Belleri et al., 2008).
  • Mice fed on a diet containing resveratrol
    • Did not show any significant inhibition of melanoma xenograft tumor growth
      • Possibly due to rapid metabolism of the compound
  • Pharmacokinetic studies in several animal models
    • Highest concentration of resveratrol in the plasma, after intravenous or oral administration is reached within the first 5 min
      • With the trans form being predominant in the plasma or tissues
  • Oral administration
    • Decreased hepatic metastatic invasion of melanoma cells inoculated intrasplenically in mice
    • This was associated with inhibition of vascular adhesion molecule-1 expression in the hepatic sinusoidal endothelium
  • P.o. trans-resveratrol
    • Did not inhibit growth of melanoma cells inoculated into the footpad of mice (Asensi et al., 2002)
  • Inhibit tumor growth in animal models of uveal melanoma
  • In vitro
    • Tumor inhibition was associated with a decrease in cell viability
    • Increase in apoptosis through the mitochondrial pathway
      • Eventual activation of caspase-3 (Van Ginkel et al., 2008).
  • resveratrol studies have yielded mixed results, both negative and positive
    • Many researchers finding no effect and others observing a strong response
      • Especially in cell culture studies
  • Difficulty in translating in vitro results to in vivo models can be largely attributed to
    • Inability of achieving and maintaining elevated levels of resveratrol in the blood (Osmond et al., 2010)
      • Continuous infusions
      • resveratrol analogs with longer half-lives (Osmond et al., 2010)

A phase I clinical trial



STING


Sho-saiko-to and baicalin

  • Down-regulated the matrix metalloproteinase-2 and -9 expression levels
  • Upregulated their inhibitor expression level in both the primary tumors and Mel-ret cells.
  • Sho-saiko-to displayed anti-tumor and anti-metastatic effects on melanoma
    • Regulation of the balance of matrix metalloproteinase and tissue inhibitor of the matrix metalloproteinase levels
  • pubmed.ncbi.nlm.nih.gov/9764846/

Silymarin

  • A flavanolignan
  • Extracted from the fruits and seeds of milk thistle (Silybum marianum L. Gaertn.)
  • Possess a protective effect against photocarcinogenesis
  • Antioxidant, anti-inflammatory and immunomodulatory properties
  • Efficacy against photocarcinogenesis (Vaid and Katiyar, 2010)
  • UV-irradiated human melanoma cells showed that silymarin protected against UV-induced apoptosis
    • Activation of the human deacetylase SIRT1
      • Involved in cell survival
  • Modulation of the cell cycle with increase in the G2/M phase
    • Possibly provides time for efficient DNA repair in silymarin-treated cells (Li et al., 2007b)
  • Silymarin can reduce UV-induced apoptosis
    • By activating AKT and MAPK pathways (Li et al., 2006)
  • silymarin enhanced the cytotoxic effect of anti-Fas agonistic antibody on human melanoma cells (Li et al., 2007a)
  • More recent study showed that silibinin
    • The major active constituent of silymarin
    • Actually prevented mitomycin C-induced apoptosis in human melanoma cells
      • Through suppression of the mitochondria-mediated intrinsic apoptosis pathway, but not the extrinsic pathway (Jiang et al., 2009)
  • Further studies are needed to understand
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3158815/#!po=6.63717


Statiny

  • Lipid-lowering agents such as statins curb these cancers' growth, even in the context of a more normal diet

Fluvastatin

Niacin

Fenofibrate

  • Could slow the expansion of V600E tumors in mice, even when they were fed a normal diet.
  • Those drugs reduced acetoacetate levels, and when the researchers injected acetoacetate to compensate, tumor growth sped up again.
  • www.sciencedaily.com/releases/2017/01/170112141359.htm
  • DOHLEDAT

Suramin

  • Dohledat

Tecfidera

  • DMF prolongs survival in melanoma mouse models and exerts its anti-metastatic efficacy through suppression of nuclear translocation of NF-?B.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602023/

Terbinafine

  • FDA-approved broad-spectrum anti-mycotic agent
  • To treat fungal colonization of nails and on the skin
  • Applied as cream, gel, solution, or spray but can also be taken orally
  • Inhibits non-competitively the squalene oxidase
    • Inhibition of the ergosterol synthesis, affects cell wall formation of the fungus
  • Radio-sensitizing effect of Terbafine in an in vivo model using murine melanoma
  • www.mdpi.com/2072-6694/13/13/3193/htm

Theanin


Trametinib

  • Inhibitor MEK

Vemurafenib

  • Zhruba 40 až 60 % melanomů je mutovaných
  • Lék se naváže na mutovaný receptor a pak složitou cestou zabraňuje šíření nemoci.
  • Účinek tohoto přípravku byl dokázán v několika klinických studiích, přičemž efekt léčby byl výborný a prodloužila se doba přežití nemocných s pokročilou formou maligního melanomu.
  • V České republice je podáván taktéž jako ipilimumab v rámci výzkumu, o hrazení pojišťovnami probíhají jednání.
  • Jednou z velmi významných signálních drah u melanomu je kaskáda MAPK/ERK,
    • Která je aktivována vznikem mutace BRAF;
    • Nejčastějším typem mutace BRAF je přitom V600E.
  • Vemurafenib, selektivní inhibitor kinázy BRAF s touto mutací
    • Schopen u nemocných s metastazujícím melanomem vyvolat vysoké procento léčebných odpovědí.
  • Ty se dostavují velmi brzy, již v prvních dnech až týdnech po zahájení léčby,
    • Dosahují více než 50 %.
  • V současné době se objevují slibné výsledky klinických studií s novými inhibitory BRAF a MEK
    • Dabrafenib či trametinib.
  • MUDr. Ivana Krajsová, MBA, Dermatovenerologická klinika 1. LF UK a VFN, Praha
  • www.farmakoterapie.cz/c3642/pokroky-v-lecbe-metastazujiciho-melanomu

Wasabi


Zyflamend

  • Nedá se koupit v ČR, ale dají se užívat byliny a účinné látky, ze kterých se skládá:
  • Supercritical fluid (CO2)
  • Hydroalcoholic extracts of the herbs:
    • Rosemary (Rosmarinus officinalis L.) = rozmarýn
    • Turmeric (Curcuma longa L.) = kurkuma
    • Ginger (Zingiber officinale Roscoe). = zázvor
    • Holy basil (Ocimum sanctum L.). = bazalka
    • Green tea (Camellia sinensis [L.] Kuntze) = zelný čaj
    • Hu zhang (Polygonum cuspidatum Siebold & Zucc.).
    • Chinese goldthread (Coptis chinensis Franch.). = koptis čínský
    • Barberry (Berberis vulgaris L.). = dřišťál obecný (obs. berberin)
    • Oregano (Origanum vulgare L.) = Oregano
    • Baikal skullcap (Scutellaria baicalensis Georgi). = Šišák bajkalský
  • Suspended in olive oil
  • Zyflamend has been shown to
    • Suppress the expression of certain genes involved in the inflammatory response and in cancer progression
      • Cyclooxygenase 1(COX-1)
      • COX-2
      • 5-lipoxygenase (5-LOX)
      • 12-LOX
  • Single-agent anticancer activity
    • Improved cancer suppression when used with hormonal and chemotherapy agents.
  • Use of this supplement is not associated with serious toxicity or adverse effects.
  • Zyflamend may inhibit the growth of melanoma cells [20]
https://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq


Blokátory protonové pumpy

  • Běžně předepisované léky na pálení žáhy
    • Pantoprazol, omeprazol, aj.
  • Snižují vylučování H+ z buněk nejen žaludku ale i u některých nádorů - mohou tak snížít jejich agresi
  • Dohledat jak je to ve vztahu k melanomu

Česnek


Hypertermie

  • Cancer cells are more fragile and vulnerable to heat with apoptosis taking place at lower temperatures compared to normal cells
  • Necrotic or heat-stressed cancer cells
    • Can function as antigens or PAMPs and thereby generate an immune-stimulating environment
  • In metastatic melanoma
    • Treated with immunotherapy, fever of 39.5°C or above was an independent factor for improved survival and objective tumor response
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC6281979/

Interferon gamma

  • Case report of extended survival and QOL in a melanoma patient with multiple brain metastases and review of literature.
  • Cureus 2017 Sperduto W et al.
    • .... v literatuře byly nalezeny informace pouze o 3 pacientech s melanomem a vícečetnými mozkovými metastázami, kteří přežili více než 10 let. Tato kazuistika popisuje případ ženy, u které ani po 11 letech od diagnostiky 3 mozkových metastáz nedošlo k rekurenci. Její léčba spočívala v podávání interferonu gama, interleukinu 2 a chemoterapii (po stereotaktické radioterapii a iniciální chemoterapii).

IL-2

  • Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen
    • Andersen R Clin Cancer Res 2016
  • Adoptivní buněčná terapie (ACT)
    • Založená na autologních tumor-infiltrujících lymfocytech (TIL)
    • V klinických studiích I. a II. fáze, vykonaných mimo Evropu, dosáhla velmi zajímavých výsledků
  • Toxické účinky související s vysokou bolusovou dávkou interleukinu 2 podávanou spolu s TIL jsou (byť jen přechodně) vážné
  • Studie I./II. fáze, ve které byl po klasické chemoterapii navozující lymfocytovou depleci vykonán transfer TIL spolu s nižšími dávkami interleukinu 2.
  • Studie se zúčastnilo 25 pacientů s progresivním mestastazujícím melanomem refrakterním na léčbu, v dobrém klinickém stavu, ve věku < 70 let a s alespoň jednou resekovatelnou metastázou.
  • Infuzi TIL předcházela standardní chemoterapie s lymfodeplečním účinkem, následovaná sníženou dávkou interleukinu 2 podanou intravenózně s postupným poklesem dávek.
  • ZÁVĚR: U pacientů s melanomem refrakterním na léčbu byla pozorována dlouhodobá kompletní odpověď (21,8 měsíce).

Interleukin-2 (IL-2)

Molecular iodine (I2)

  • And 6-iodolactone (6-IL)
  • Systematically tested on many different human cell lines, including
    • Neuroblastoma, 4 mammary cancer lines, normal mammary cells, lung, 2 glioblastoma cell lines, melanoma, 2 pancreatic cell lines, and colon carcinoma cells
  • After a 2-day culture with molecular iodine (I2)
    • All cell lines were inhibited except for colon cancer.
    • Neuroblastoma cells underwent the most complete inhibition
    • MCF-7 breast cancer cells the second most sensitive
  • Similar inhibitory effects were found with 6-IL
  • Mechanism of action included
    • Inhibition of endothelial growth factor in this experiment
    • Prior experimentation by the same group found that the inhibition is most likely due to changes in the mitochondrial membrane potential, resulting in apoptosis
      • An effect that was completed thwarted with the addition of N-acetyl-cysteine
  • www.naturalmedicinejournal.com/journal/2014-06/iodine-and-cancer
Takže by se dal předepsat jodid draselný 2,5% roztok k užití 1-3 x denně, v lepším případě i radioaktivní jód a dále by se to dalo potencovat ozařováním. Kontrolovat u toho hormony štítice a při elevaci TSH podat hned malou dávku Euthyroxu.



Curcumin + catechin

Mice

  • Maximal effect observed
    • Comparation of p.o. polyphenolic compounds on inhibition of lung metastasis compared in mice inoculated with melanoma cells

In vitro studies curcumin and catechin

  • Inhibited the invasion of melanoma cells by inhibition of MMPs
    • Thereby inhibiting lung metastasis (Menon et al., 1999)

Kyanidy

  • Jablečné jádřince
  • Hořké mandle
  • Celá řada dalších zdrojů
  • Důležité je však dávkování- lze se i otrávit

Lékořice

  • Vida Dr. Landa lze objednat i čistý lékořicový čaj

Alpha-mangostin

SK-MEL-2 and SK-MEL-30 melanoma cells

  • ?-mangostin treatments resulted in IC50s of 8.14 and 7.78 µM, respectively [37]. Xia et al. used the kinase inhibitor Sorafenib in combination with ?-mangostin and observed that the combination more potently inhibited colony formation and the phosphorylation of AKT and ERK than either agent alone [37].
  • www.sciencedirect.com/science/article/abs/pii/S1043661821006162

Alpha-mangostin

B16-F10 melanoma cells treated with ?-mangostin revealed that their proliferation was significantly affected at concentrations > 5 µM and that their melanin content and cell differentiation abilities were decreased [44]. The metastatic potential of melanoma cells decreased in a dose-dependent manner and the levels of MMP-9 decreased. Proteomic analysis revealed proteins involved with regulation, biosynthesis, and transportation were upregulated in ?-mangostin-treated cells [44]. ?-Mangostin was also cytotoxic to SK-MEL-28 and A-431 skin cancer cells, increased caspase activity and promoted apoptosis, inhibited their migration, invasion, and adhesion, and decreased the levels of MMP-2, MMP-9, and AKT [45], [46].

Melatonin has a scientific name of N-acetyl-5- methoxytryptamine

  • For cancer of the breast, brain, lung, prostate, head, neck, and gastrointes?tinal tract
  • Melatonin is also used for jet lag, insomnia, nicotine withdrawal, headache, hypertension, and other conditions.
  • Can decrease the incidence of cytokine-induced hypotension for patients with cancer.
    • Interleukin-2 and tumor necrosis factor
      • Examples of cyto?kines (Lissoni et al., 1996a)
  • Quick-release melatonin
    • May be beneficial in decreasing potential sleep disorders associated with conditions such as
      • Thrombocytopenia induced by chemotherapy or interleukin-2 (Bregani et al., 1995; Micromedex Healthcare Series, 2003; Lissoni et al., 1995, 1996b, 1999).
  • Beneficial in stabilizing disease for adults with solid tumors who do not respond to treatments or cannot receive treatments (Micromedex Healthcare Series; Lissoni et al., 1991, 1994a).
Herbs or Natural Products That Decrease Cancer Growth Part One of a Four-Part Series; Muriel J. Montbriand, PhD, RN; Downloaded on 08 28 2019. Single-user license only. Copyright 2019 by the Oncology Nursing Society. For permission to post online, reprint, adapt, or reuse, please email pubpermissions@ons.org


Melatonin + interleukin-2

  • Seems to improve survival for patients with advanced solid tumors of the breast, gastrointestinal tract, kidney, liver, and lung and melanoma

Melatonin + triptorelin pamoate

  • For prostate cancer, radiotherapy for glioblastoma

Micromedex

  • melatonin + interferon for renal cell cancer (Micromedex Healthcare Series).

Adverse effects of melatonin

  • Headaches, transient depression,
  • Daytime fatigue and drowsiness,
  • Dizziness, abdominal cramps,
  • Irritability (Micromedex Healthcare Series, 2003; Wagner, Wagner, & Hening, 1998)
  • Reduces alertness (Dollins et al., 1993, Micromedex Healthcare Series)
  • Commercially available melatonin usually is synthesized in laboratories
    • Possible contamination
  • Optimal safe dose has not been established
  • 20-50 mg along with radiation or chemotherapy has been used for cancer treatment (Brzezinski, 1997; Micromedex Healthcare Series, 2003).
Herbs or Natural Products That Decrease Cancer Growth Part One of a Four-Part Series; Muriel J. Montbriand, PhD, RN; Downloaded on 08 28 2019. Single-user license only. Copyright 2019 by the Oncology Nursing Society. For permission to post online, reprint, adapt, or reuse, please email pubpermissions@ons.org



Radiation therapy

  • High-energy ray beams are directed to tumors to shrink cancer cells.
  • It is mostly used for melanomas in Stage 3 or 4 that have spread to distant lymph nodes or organs, mainly to slow down and relieve symptoms of advanced melanoma, which may have spread to the brain or bones.
  • Radiation therapy may also be used to prevent or destroy recurring melanoma.

Radioterapie s radioaktivním jodem

  • Positron emission tomography relies on the nonspecific accumulation of 18fluoro-2-deoxy-d-glucose (FDG) in metabolically active MM lesions, the detection of metastatic MM by ISG is specific.
  • The MAbs that are used for ISG may also have therapeutic potential

Standardem léčby pacientů s pokročilým maligním melanomem


Veganská dieta

  • S vynecháním cukru, omezením škrobů
  • Nízkotučná
  • S dostatkem cibule a česneku


Vitamín B17

  • Zdroj kyanidů

Zelený čaj

  • Vynechat krátce před a po podání vitamínu C i.v. pro riziko oxlátových kamenů v ledvinách
O úroveň výše

Poslední aktualizace: 10. 12. 2023 21:19:52