MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Terapie, podpůrné postupy

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.

2-DG + 3-BrPA (anti-glycolytic agent)

  • MiaPaCa2 and Panc-1 pancreatic cancer cells manifest energy depletion
  • Increased cell necrosis
  • Glycolysis inhibition [18]

6-Sholagol

Nádory slinivky: ginger extract has potent anticancer activity against pancreatic cancer cells by inducing reactive oxygen species (ROS)-mediated apoptosis (Akimoto et al., 2015). In fact, ethanol extract of ginger suppressed cell cycle progression and consequently induced death of human pancreatic cancer cells, Panc-1, AsPC-1, BxPC-3, CAPAN-2, CFPAC-1, MIAPaCa-2 and SW1990, and mouse pancreatic cancer cells, Panc02 (Akimoto et al., 2015). The extract markedly increased the microtubule-associated protein light chain (LC)3-II/LC3-I ratio, decreased sequestosome 1 (SQSTM1)/p62 protein, and enhanced vacuolization of the cytoplasm in Panc-1 cells (Akimoto et al., 2015). The cytotoxic effect of the ethanolic extract of ginger was reported toward cholangiocarcinoma CL-6 cells (Plengsuriyakarn et al., 2012). Experimental studies also showed that ginger as well as 6-gingerol and 6-shogaol exerted cytotoxic effects against gastrointestinal cancer cells (Prasad and Tyagi, 2015). The anticancer activity of ginger has been attributed to its ability to modulate several signaling molecules like NF-?B, STAT3, MAPK, PI3K, ERK1/2, Akt, TNF-?, COX-2, cyclin D1, cdk, MMP-9, survivin, cIAP-1, XIAP, Bcl-2, caspases, and other cell growth regulatory proteins (Prasad and Tyagi, 2015). Qi et al. (2015) have observed that 6-shogaol (15 mg/kg) significantly inhibited colorectal tumor growth in a xenograft mouse model. The investigators showed that 6-shogaol significantly inhibited HCT-116 cells and SW-480 cells’ proliferation with IC50 values of 7.5 and 10 µM, respectively (Qi et al., 2015). www.sciencedirect.com/topics/neuroscience/shogaol

Deferasirox

  • Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action

Myši

  • Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO.
  • Deferasirox was generally similar or slightly more effective than DFO
    • At mobilizing cellular 59Fe
    • Inhibiting iron uptake from human transferrin depending on the cell type
  • Deferasirox potently inhibited DMS-53 xenograft growth in nude mice
    • When given by oral gavage
    • With no marked alterations in normal tissue histology.
  • Deferasirox increased expression of the metastasis suppressor protein N-myc
    • Downstream-regulated gene 1
    • Upregulated the cyclin-dependent kinase inhibitor p21CIP1/WAF1
    • Decreasing cyclin D1 levels
  • Increased the expression of apoptosis markers
    • Cleaved caspase-3
    • Cleaved poly(ADP-ribose) polymerase 1
  • Deferasirox is an orally effective antitumor agent against solid tumors.
  • Mitochondrially targeted deferasirox
    • Kills cancer cells via simultaneous iron deprivation and ferroptosis induction.
  • Sukanya B Jadhav1,2*, Cristian Sandoval-Acuna1*, Yaiza Pacior1,2, Kristyna Klanicova1,2, Kristyna Blazkova1
  • www.biorxiv.org/content/biorxiv/early/2024/01/20/2024.01.17.575692.full.pdf
  • Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
  • Faculty of Science, Charles University, Prague, Czech Republic
  • Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic

Deferasirox + gemcitabine

  • RR is constructed from large RRM1 and small RRM2 subunits.
  • RRM1 is constantly expressed throughout the cell cycle
  • RRM2 is initiated during S-phase
    • Degraded following M-phase
  • Catalytic activity of RR is dependent on a dinuclear iron site in the RRM2 subunit;
    • RRM2 requires iron for stabilization
  • RR regulation involves the control of RRM1 and RRM2 activity and expression
    • Absence of a constant supply of iron to RRM2 results in RRM1 inactivation
    • Synergistic effect between hydroxyurea, a RR inhibitor, and gemcitabine on gemcitabine-resistant cells
  • Synergistically inhibits pancreatic cancer cell growth in vitro and in vivo
  • GEM+DFX antiproliferative activity + induced apoptosis in pancreatic cancer cells in vitro.
  • GEM still remains a key drug for pancreatic cancer today; however, the most important problem is gemcitabine resistance.
  • The levels of GEM’s active derivate gemcitabine triphosphate
    • Must comprise a sufficient proportion of the cellular pool of deoxynucleotides (dNTPs) to be efficiently incorporated into the DNA.
    • Expansion of naturally occurring dNTPs in the nucleotide pool leads to GEM resistance.
  • RR plays an essential role in the maintenance of the deoxyribonucleotide pool
  • RR upregulation also leads to GEM resistance
    • Clinically relevant in lung, breast cancer
  • In pancreatic cancer, interestingly, RRM1 levels were inversely correlated with patient survival
  • Antiproliferative activity of iron chelators first demonstrated in leukemia in 1986
    • Antiproliferative activity of DFX has been investigated in various cancers
  • Antiproliferative activity by
    • Suppressing RR expression and activity
    • Potentiated the effect of GEM by decreasing the competition between GEM and deoxycytidine triphosphate
  • GEM+DFX showed therapeutic advantages without serious side effects over single-agent GEM
  • Method might turn out to be applied to other cancer like
    • Non-small cell lung cancer,
    • Ovarian cancer
    • Bladder cancer in future

DFX + GEM + albumin-bound paclitaxel

  • Possibly have therapeutic advantages over albumin-bound paclitaxel with GEM in pancreatic cancer

DFX + fluorouracil in FOLFIRINOX



Immune checkpoint inhibitors

  • Blocking proteins on immune cells that cancer cells use to evade the immune system.

Targeted therapies

  • Target specific molecular pathways or abnormalities that are involved in cancer cell growth and survival.

Anti-angiogenic therapies


Gene therapies

  • Introduction of normal genes into cells to correct genetic defects that may be contributing to cancer growth.

Photodynamic therapy

  • Photosensitizing agent that is activated by light, leading to the destruction of cancer cells.

Radioimmunotherapy

  • Radiolabeled antibody that is directed against a specific protein on cancer cells.

Stem cell therapies

  • Stem cells, which have the ability to differentiate into various cell types
    • Replace cancer cells or stimulate the immune system to attack cancer cells.

Proton pump inhibitors (PPIs)

  • PPIs may have potential as a treatment for pancreatic cancer.
  • One study published in the journal Cancer Research
    • PPI treatment was associated with a reduced risk of pancreatic cancer in a group of individuals with a history of acid reflux.
  • May have potential as a treatment for pancreatic cancer
  • Not currently approved by the FDA for the treatment of pancreatic cancer

Curcumin

  • In turmeric
  • Anti-inflammatory and antioxidant properties
  • Potential as a treatment for pancreatic cancer, although more research is needed.

Vitamin D

  • Low levels of vitamin D have been linked to an increased risk of pancreatic cancer.
  • Supplementation with vitamin D may help to reduce the risk of developing pancreatic cancer or improve outcomes in people with the disease.

Omega-3 fatty acids

  • Anti-inflammatory properties and may help to reduce the risk of pancreatic cancer.

Methylsulfonylmethane (MSM)

  • Anti-inflammatory and antioxidant effects
  • Studies have suggested that it may have potential as a treatment for pancreatic cancer

Ivermectin and gemcitabine combination

  • Induces apoptosis in pancreatic cancer

Ivermectin

  • Suppresses pancreatic cancer via mitochondria dysfunction
  • Ivermectin in combination with gemcitabine on pancreatic cancer
    • Is more effective than gemcitabine alone.
  • Ivermectin-gemcitabine combination
    • Inhibited cell proliferation via G1 arrest of the cell cycle
      • Down-regulated cyclin D1 expression through mTOR/STAT3 signaling pathway
  • Ivermectin-gemcitabine induced apoptosis by ROS generation and reduction of mitochondrial membrane potential (MMP), and blocked mitophagy.
  • In vivo experiments also confirmed that ivermectin-gemcitabine groups
    • Significantly suppressed the tumor growth of pancreatic cancer compared with gemcitabine alone groups.
  • Ivermectin has a synergistic effect with gemcitabine in preventing cancer progression
  • Could be a potential antitumor drug for the treatment of pancreatic cancer.
  • aacrjournals.org/cancerres/article/82/12_Supplement/2320/701043/Abstract-2320-Ivermectin-suppresses-pancreatic

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

Plitidepsin

  • Exhibits antitumor, antiviral and immunosuppressive activities. It shows promise in shrinking tumors in pancreatic, stomach, bladder, and prostate cancers
  • en.wikipedia.org/wiki/Plitidepsin

Pyrvinium Pamoate


-Quercetin treatment resulted in the upregulation of miRNA let-7c

    • Inhibits pancreatic cancer progression
      • By post-transcriptional activation of Numb-like (NumbL) gene

Tecfidera

Other cancer cell lines, including colorectal cancer [37], cervical cancer [112], lung adenocarcinoma [113] and pancreatic carcinoma [113] are also sensitive to DMF-induced cytotoxicity. These studies suggest that FAE could be broadly utilised as an anti-cancer therapy.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602023/

Adjuvant chemoradiation therapy following resection

  • Patients after resection and with no evidence of relaps or metastasis
    • May not be optimal
      • Cca 25% of patients are unable to complete adjuvant course or is prolonged
        • X recovery from the surgery [3]
  • Nonresectable disease
    • Chemotherapy with or without radiation
      • Palliative purposes [3]
      • Beneficial for some patients [3]

Antiangiogenic agent + chemotherapy

  • Chemotherapy is more effective
  • Bevacizumab with the EGFR tyrosine kinase inhibitor erlotinib [6]

Bevacizumab - Avastin

  • A monoclonal anti–vascular endothelial growth factor antibody
  • Might lower tumor interstitial pressure
  • Could increase chemotherapy delivery to the tumor bed and thus improve efficacy

CUMIN - Cuminum cyminum

  • Flowering plant in the family Apiaceae
  • Thymoquinone (TQ) is the most abundant component of black cumin seed oil
    • Suppress tumor cell proliferation, including
      • Colorectal carcinoma,
      • Breast adenocarcinoma,
      • Osteosarcoma,
      • Ovarian carcinoma,
      • Myeloblastic leukemia,
      • Pancreatic carcinoma (Gali-Muhtasib, Roessner, and Schneider-Stock 2006)
  • Normal cells appear to be slightly resistant to TQ (Worthen, Ghosheh, and Crooks 1998)
  • Downregulation in Bcl-xL, cyclin D1, and VEGF (Aggarwal et al. 2008)
  • Induce free radical formation in tumor cells
  • Effective in inhibiting human umbilical vein EC migration, invasion, and tube formation
    • Role in angiogenesis (Yi et al. 2008)
  • TQ (6 mg/kg/day) was also found to prevent tumor angiogenesis in a xenograft human prostate cancer (PC-3) model (Yi et al. 2008) [18]
www.ncbi.nlm.nih.gov/books/NBK92774/

Chloroquine (autophagy blocker)

  • Significant growth suppression of pancreatic cancer cells
  • Tumor regression
  • Prolonged survival
  • Increased total and mitochondrial ROS levels, along with DNA damage
  • Severe decrease in oxidative phosphorylation
  • Significant elevation in uptake of glucose and lactate production [18]

K-Ras(G12D) doxy withdrawal

  • Transgenic mice
  • Doxy induction provokes acinar-to-ductal metaplasia and PanIN lesions within 2 weeks
  • Doxy withdrawal leads to:
    • Rapid tumor regression
    • Morphological deterioration of tumor cells
    • Rapid degeneration of stromal elements
    • Decreased tumor cell proliferation
    • Increased apoptosis
    • Significant reduction in expression levels of several glycolytic enzymes
      • Not accompanied by significant alterations in levels of TCA cycle intermediates [18]
    • Marked reduction in nonoxidative PPP-specific metabolites S7P and SBP
      • Reduction in the flux of glucose into the nonoxidative arm of the PPP [18]

C. perfringens

  • Shown to be capable of colonizing in advanced stages of selective pancreatic cancers
  • Inducing progressive necrosis in the tumours

Docosahexaenoic acid (DHA) diet (omega-3 fatty acid)

  • Recurrence and proliferative index of pancreatic precancer in EL-K-Ras mice
    • Decreased in mice maintained on DHA diet
  • DHA treatment in tissue culture
    • Resulted in a dose-dependent reduction in:
      • Cell cycle progression through both G1/G0 blockage [18]
      • Induction of programmed cell death [18]

Erlotinib

  • FDA in 2005 [24]

Ethyl pyruvate (pharmacological inhibitor of nuclear HMGB1)

  • In vivo
    • Tumor cell growth was significantly reduced [18]
  • In vitro
    • Increased apoptotic signal (PARP)
    • Decreased signals of inflammation (p-p65), and autophagy (LC3-II)
    • Reduced ATP production [18]

Everolimus (rapamycin analog)

  • Inhibition of cell proliferation and glycolysis
  • Induction of apoptotic cell death of Panc-1 human pancreatic cancer cells
  • Upregulation of levels of miR-143 transcripts
  • Decrease in HK2 transcripts levels [18]

FX11 (inhibitor of LDHA)

  • Cell growth inhibition of P198 human pancreatic cancer cells
    • Increased sensitivity under hypoxia
  • Inhibition of pancreatic tumor xenograft progression
  • Reduction of ATP levels
  • Induction of marked oxidative stress
  • Cell death
  • Decreased NAD+ recycling (increased NADH/NAD+ ratio) [18]

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

  • Naturally occurring flavonoid
  • Abundant in several fruits and vegetables, including strawberry, apple, persimmon, grape, onion and cucumber
  • Multiple biological activities including anti-proliferative, pro-apoptotic, neuroprotective and anti-oxidative activities
  • Suppress the proliferation of a wide variety of tumor cell, including
    • Prostate cancer
    • Liver cancer
    • Colon cancer
    • Leukemia cells
  • Inhibit
    • Mitogen-activated protein kinase (MAPK)
    • Nuclear factor (NF)-kappaB signaling pathways in various type of cancer cell
      • Colon and pancreatic cancer
  • Reduce the invasive and migratory capacity of the A549 human lung cancer cell line
    • Via the extracellular signal-regulated kinase (ERK) signaling pathway
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5792763/

Folfirinox

  • Chemotherapy regimen
  • Four drugs
  • More effective than gemcitabine
  • Side effects
  • Only suitable for people with good performance status
  • Increased survival by a few months [24]

Gemcitabine

  • FDA in 1997
  • In people with advanced pancreatic cancer
    • Improvements in quality of life
    • A 5-week improvement in median survival
  • Standard for about a decade
  • Number of trials testing it in combination with other drugs failed [24]
  • Méně NÚ než Folfirinox a nab-paclitaxel

Emcitabine + erlotinib

  • Increase survival modestly [24]

Gemcitabine + FOLFIRINOX

Gemcitabine + Abraxane

HMGB1-knockdown by shRNA

  • Reduction in autophagy
  • Increase in sensitivity of PDAC-derived cells to apoptosis
    • Induced by melphalan [18]


Palbociclib (Ibrance)

  • CDK4 a 6 inhibitor

Kurkumin

Several combination trials currently ongoing

  • In combination with neoadjuvant capecitabine and radiation in rectal cancer (NCT00745134)
  • With FOLFOX in inoperable colon cancer (NCT01490996)
  • curcumin monotherapy in advanced pancreatic cancer (NCT00094445)
  • curcumin can exert anticancer properties via multiple targets
    • Concentration needed to achieve these results may not be achievable in vivo
    • Several ongoing efforts evaluating newer
      • Nanoparticle curcumin formulations
      • Combinations with piperine to improve bioavailability [24]

Synergism

  • 1–10 µM curcumin and
    • 5-fluorouracil (5-FU)
    • Paclitaxel in PC-3 cells has been observed [24]
  • Potentiate the cytotoxicity of chemotherapy agents in other cell lines [24]
  • Curcumin-mediated MDM2 downregulation
    • Sensitized the PC3 prostate cancer cell line to both
      • Gemcitabine
      • Radiation in cell line and mouse xenograft models [24]

[24] Complementary and Alternative Medicines in Prostate Cancer: From Bench to Bedside? Samuel J. Klempner and; Glenn Bubley; Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Telephone: 617-667-9296; Fax: 617-667-4809; e-mail: sklempne{at}bidmc.harvard.edu; Received March 1, 2012.; Accepted May 1, 2012.; First published online in THE ONCOLOGIST Express on May 22, 2012.


K. alfalipoová + hydroxycitrát

Between 2009 and 2011, 11 patients with histologically-proven malignant disease were treated according to the standard protocol in use for their cancer type and stage (11). In addition to their normal chemotherapeutic regimen, a combination of ?-LA and HCA was administered. Informed consent was obtained and efficacy results and side-effects were registered. The minimum oral dose of ?-LA administered was 0.4 g/day, and the maximum dose was 1.8 g/day. The minimum dose of HCA was 1.2 g/day and the maximum dose was 3 g/day.


The recorded side-effects were related to the respective chemotherapies administered, except for gastrointestinal disorders of mild intensity. Three patients out of five treated with higher doses of ?-LA and HCA, 1.8 g/day and 3 g/day, respectively, had grade 1 to 3 side-effects, including stomach pain, diarrhea and nausea, and two patients reported weight loss.
These side-effects disappeared on using proton pump inhibitors or by reducing the dose. Seven patients tolerated the ?-LA-plus-HCA treatment without side-effects. Two of these patients were administered proton pump inhibitors as part of their treatment, but the other five had no accompanying treatment. The minimum duration of treatment was two months, while the maximum duration was 44 months.
Most of the patients receiving treatment for more than six months displayed partial regression or stabilization. Out of eleven patients, disease in five was characterized by partial regression, three were characterized by stable disease, and three by progression.
One patient affected by a pancreatic adenocarcinoma with liver metastases displayed tumor regression during a few months. After she decided to stop her treatment, she died. She had survived 18 months after starting this treatment (10). A patient with parotid gland carcinoma also responded to this therapy, with regression of primary tumor and metastases. However, the cancer finally recurred. Another patient is alive and well at four years after the diagnosis of widely metastatic bulky peritoneal metastasis of a colonic carcinoma (11).
In the meantime, Berkson et al. (12, 13) treated four patients with pancreatic cancer with a combination of ?-LA and naltrexone. The results were strikingly positive, and the first patient treated was alive and well 78 months following the initiation of treatment.
Another group synthesized, CPI-613, an ?-LA analog, and reported activity in one patient with metastatic pancreatic adenocarcinoma (14).

Leucovorin/5-FU


Alpha-mangostin

alpha-mangostin affects the ability of cancer cells to migrate and invade other cells, which has implications in promoting the epithelial to mesenchymal transition of cells and is often regulated by the expression of matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, and the epithelial marker protein E-cadherin. BxPC-3 and MIAPaCa-2 pancreatic cancer cells treated with 5 uM of alpha-mangostin showed decreased cell viability and decreased migratory, invasive, and proliferative abilities [42]. MMP-2 and MMP-9 mRNA and protein expression levels were increased after treatments with alpha-mangostin while the E-cadherin levels were decreased, as is common when the migratory and invasive capabilities of cancer cells are affected [42]. A later study reported consistent results showing that alpha-mangostin decreased the expressions of MMP-2 and MMP-9 in BxPc-3 and Panc-1 cells, that G0/G1 cell cycle arrest was induced, and that the PI3K/AKT pathway was suppressed
  • In pancreatic cancer cell lines MIA PaCa-2 and PANC-1, ?-mangostin affected cell viability with IC50s 11.7 and 25 uM after 48 h and 4.2 and 10.2 uM after 72 h, respectively [96]. Cell death was promoted in both cell lines as evidenced by increases in pro-apoptosis and pro-autophagy protein expression levels as well as increases in levels of miRNAs involved in apoptosis, including miR-18a. Co-treatments with gamma-mangostin and gemcitabine, a commonly used chemotherapy agent for pancreatic cancer, affected cell viability more strongly than gemcitabine treatments alone, indicating that gamma-mangostin may sensitize pancreatic cancer cells to treatment [96].
  • www.sciencedirect.com/science/article/abs/pii/S1043661821006162

Metformin

  • Does not or poorly permeates the plasma membrane
  • Is not metabolized but it is accumulated in tissues such as:
    • The liver
    • The kidneys,
    • The salivary glands
    • The gastrointestinal tract
  • 80% of the elimination of metformin occurs by the urinary tract [21]
  • Appears to accumulate in red blood cells
    • With a much longer elimination halflife: 17.6 hours [21]
  • Decreases cancer risk and overall cancer mortality among the diabetic population
  • Inhibition of ATP and ROS production
  • Inhibition of IRS-1/Akt/mTORC1 axis
  • Anti-inflammatory effects
  • Cell cycle arrest
  • Inhibition of general transcription factors [21]
  • Decrease in adenosine triphosphate (ATP) production
    • Increase in adenosine monophosphate (AMP) levels
      • Activate the kinase AMP-activated protein kinase (AMPK) [21]
  • High AMP and adenosine diphosphate (ADP) levels
    • Permissive for AMPK activation
    • AMP promotes AMPK phosphorylation at its catalytic ?-subunit (Thr-172) by:
      • Its upstream kinases liver kinase B1 (LKB1)
      • Calcium/calmodulin-dependent protein kinase kinase-beta (CaMKKß)
      • Alossteric activation and prevents dephosphorylation by:
        • protein phosphatase type 2a (PP2a)
        • protein type 2c (PP2c) phosphatases
    • ADP also protects AMPK from dephosphorylation
  • metformin-induced decline in endogenous ROS levels
    • Implicated to be involved in cancer risk reduction
  • AMPK activate the tumor suppressor protein 53 (p53) (Ser-15)
    • Inducing cancer cell cycle arrest and senescence
  • P53 has been shown to increase AMPK activity
    • Leads to mammalian target of rapamycin (mTOR) inhibition in vitro
  • Cause a G0/G1 cell cycle arrest
    • Decreasing the expression of cyclin D1
    • Preventing the phosphorylation of pRb (its inactivation) [21]
  • Metformin-induced AMPK activation
    • Phosphorylate insulin receptor substrate-1 (IRS-1) at Ser-794
      • Decreased recruitment of the p85 subunit of phosphoinositide-3-kinase (PI3K)
        • Impairing the IGF-stimulated PI3K/protein kinase B/ mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) signaling pathway [21]
  • Inhibit the crosstalk between the:
    • Insulin/IGF receptor
    • G protein-coupled receptor (GPCR) signaling
      • Resulting in the inhibition of mTORC1 [21]
  • Biguanides inhibit the Rag-dependent mTORC1 signaling by:
    • Preventing the colocalization of mTORC1
    • With its activator Ras homolog enriched in brain (Rheb) [21]
  • Rags
    • GTPases comprised of four proteins:
      • RagA, RagB, RagC and RagD [21]
    • Heterodimerize to activate mTORC1 upon amino acid stimulation
    • Bind to the Ragulator complex made up of:
    • Localizing mTORC1 from the perinulcear compartment (where Rheb is located)
      • Into the cytoplasm
      • Preventing Rheb activation of mTORC1 [21]
  • Increases the expression of the mTOR inhibitor
    • Regulated in development and DNA damage responses (REDD1)
      • Consequently down-regulating mTOR signaling [21]
  • In human monocytes, metformin prevents TNF production at micromolar concentrations in:
    • Lipopolysaccharide (LPS) and LDL [21] [21]
  • Activation and phosphorylation of AMPK
    • Dependent on the serine-threonine kinase
    • Ataxia telangiectasia mutated (ATM)
    • A checkpoint that responds by activating the DNA damage response to:
      • Double-strand breaks
      • Oxidative stress [21]
    • Aktivating of numerous downstream targets:
      • P53
      • Checkpoint kinase 2 (Chk2)
      • Breast cancer 1 (BRCA1)
      • Fanconi anemia
      • Complementation group 2 (FANCD2)
      • Nijmegen breakage syndrome 1 (Nbs1)
      • P53 upregulated modulator of apoptosis (Puma)
      • Phorbol-12-myristate-13-acetate-induced protein 1 (Noxa)
      • BCL2-associated X protein (Bax) [21]
  • Induces nuclear degradation
  • Decreases expression of Sp proteins
  • Decreases expression of transcription factors for genes involved in:
    • Cell proliferation (cyclin D1)
    • Metabolism (FAS)
    • Apoptosis
      • B-cell lymphoma 2 () bcl-2) [21]
      • Survivin
    • Angiogenesis
      • Vascular endothelial growth factor (VEGF)
      • Its receptor VEGFR1 [21] [21]
  • Inhibit glycolysis in various cancer cell lines [21]
  • Inhibitor of complex I of the electron transport chain [21]
  • Ability to increase fatty acid ß-oxidation in adipocytes [21]
  • Ability to inhibit hepatic lipogenesis [21]
  • Tumor growth inhibition in vitro and in vivo
    • Down-regulation of Sp (specificity protein) transcription factors
      • Consequent down-regulation of the Sp-regulated genes [21]
  • Impair tumor development in pancreatic cancer in xenografts models [21]
  • Inhibits glucose-derived fatty acid synthesis in the context of:
    • Available acetyl-CoA
    • Presence of K-rasmutation in pancreatic cancer cells
    • Obesity
    • Metabolic syndrome
    • Diabetes [21]
  • May be useful + with lipid lowering and chemotherapeutic agents [21]
  • Up-regulation of fatty acid synthase (FAS)
    • Enzyme that catalyzes the terminal step in palmitate synthesis
    • Is associated with:
      • Increased resistance to gemcitabine [21]
      • Increased resistance to radiation treatments in human pancreatic cancer tissues [21]
  • Modulate the insulin receptor (IR) in cholesterol (chol)-treated human hepatoma cells, HepG2 [21]
  • metformin is a charged biguanide
    • Requiring cell surface transport protein for its influx [21]
  • High energy diet promotes tumor growth
    • metformin decreases tumor volume only in highenergy fed animals [21]
      • Vivomodels of lung and colorectal xenografts
  • Strong tumor growth delay effect of metformin in pancreatic cancer xenograft models
    • Doses used (>200mg/kg, i.p.) may not be clinically relevant [21]
    • Anti-diabetic dose versus the anti-cancer dose versus preventive [21]
  • Data in humans using metformin for treatment of cancers
    • Shows some benefit at clinically used doses
    • Certainly not as impressive as pre-clinical high dose metformin [21]
  • We did not find any ongoing human study using very high doses (beyond 3000 mg/day) primarily to treat cancers. [21]
  • Decreasing hepatic gluconeogenesis
  • Activating insulin receptor tyrosine phosphorylation
  • Decreasing intestinal glucose absorption
  • Increasing skeletal and adipose tissue glucose uptake
  • Nude mice 250 mg/kg/day for three consecutive days increased:
    • Glycolytic enzymes hexokinase to the mitochondria
    • Phosphofuctokinase to F-actin in mice hearts
    • Activation and up-regulation in glycolysis
      • Increasing cardiac glucose utilization
        • Cardio protective effects
  • Welltolerated drug
  • Lactic acidosis as a reported serious side effect [21]
    • Has been questioned last years [21]
  • Inhibits the gene expression of carnitine palmitoyltransferase 1 (CPT1)
    • A mitochondrial enzyme
    • Ratelimiting step in long-chain fatty acid ß-oxidation
    • CPT1 catalyzes the transfer of acyl-CoA to the carnitine hydroxyl group
      • Forming acyl-carnitine
  • Prevents the nuclear activation of:
    • Sterol-regulatory element-binding protein 1c isoform (SREBP-1c)
    • SREBP-2 sterol-regulatory element-binding protein 2 isoform (SREBP-2)
      • Transcription factors that induce the expression of enzymatic genes involved in:
  • Decreases the activities of:
    • 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR)
    • Acyl coenzyme A:cholesterol acyltransferase (ACAT)
  • Decreases the gene expression of steroyl-CoA desaturase 1 (SCD1)
    • Enzyme responsible for desaturation of:
      • Stearic acid (18:0) into oleic acid (18:1 n-9)
      • Palmitic acid (16:0) to palmitoleic acid (16:1 n-7).
  • Decreases the protein expression of enzymes involved in fatty acid synthesis:
    • FAS
    • Acetyl-CoA carboxylase (ACC)
    • ATP citrate lyase (ACLY) [21]
  • Inhibitor of complex I of the ETC [21]
    • Some impairment in mitochondrial function in human-derived non-malignant and in cancer cells [21]
  • Metformin has slow permeation properties across the inner mitochondrial membrane
    • Longer incubation periods [21]
  • Block activation or expression of key lipid biosynthesis enzymes such as:
    • ACC, FAS, HMGCR [21]
  • Enhance expression of regulators of:
    • mitochondrial biogenesis
    • Peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) [21]
  • metformin-induced inhibition of respiration
    • Blocked by the addition of palmitate in 3T3-L1 adipocytes
    • Can be reversed by the addition of fatty acids
  • Normoglycemic effects of metformin
    • Attributed to its ability to prevent fatty acid oxidation in liver
      • Decreases acetyl-CoA, ATP and reducing equivalents’ availability for hepatic gluconeogenesis
    • V.s. mediated by a reduction in the expression of:
      • The carnitine palmitoyltransferase I gene [21]
      • In impairment in long fatty acid chain transport
        • From the mitochondrial outer membrane
        • Into the matrix where ß-oxidation takes place [21]
  • AMPK-mediated suppression of SREBP-1c
    • Prevent lipogenesis in an insulin resistant mouse model
    • Decrease in hepatic SREBP-1 expression in mice fed a high fat (60% lipids) diet
  • Physiologically relevant dose of metformin
    • Impairs glucose utilization in pancreatic cancer
    • By inhibiting FAS when cholesterol synthesis is limited
  • K-rasmutation cnacer cells
    • Require de novofatty acid (FA) synthesis for lipids ('lipogenic cells')
    • Were unable to synthesize FA from acetyl-CoA in the presence of:
  • metformin (100 µM) using an acute treatment of 24 h
    • Decreases de novolipid synthesis via the FAS pathway in pancreatic adenocarcinoma only when:
      • A) the glucose-derived acetyl-CoA is made available for FA synthesis
        • By inhibition of cholesterol synthesis (addition of exogenous cholesterol) ---b) K-ras mutation is present [21]
  • Non-lipogenic cancer cells harboring a K-ras G12C mutation with suppressed cholesterol synthesis
    • Significantly more sensitive to the growth inhibiting effects of metformin
      • Than tumor cells containing wild-type K-raswith normal cholesterol synthesis [21]
  • Restauroval tvorbu paměťových T-lymfocytů [26]
  • Selektivní účinek metforminu na nádorové kmenové buňky [26]

Časování chemoterapie - metronomic dosing

  • More steady
  • Can result in fewer side effects
  • Better tolerability
  • Increased efficacy due to the increased dose density [6]
  • May have antiangiogenic properties due to its effects on endothelial cells
    • Especially with paclitaxel and perhaps also with 5-FU [6]

Metronomic dosing of POLF

  • U ca pankreatu IV. stupně

Mitomycin C



Neem leaf extract

  • Rel protein-regulated cell death/radiosensitization in pancreatic cancer cells

Neoadjuvant chemoradiation therapy before resection

  • Early treatment of micrometastatic disease
  • Delivery of chemotherapy and/or radiation to a well-vascularized tumor
  • V.s. healthier patient
  • Additional time for aggressive tumors to declare themselves
  • Improvement of R0 resection rates
    • Decrease of local failure rates [3]
      • Several studies have shown a benefit
      • Negative pathologic margins (R0)
        • 6% for 3-year actuarial survival
      • Positive margins
        • 22% for 5-year actuarial survival [3]
  • Subset of about 7% of patients
    • no metastatic disease
    • Borderline resectable category [3]


Niclosamide

  • Der inhibitorische Effekt von Niclosamid auf humane Pankreaskarzinom-Zelllinien und Analyse der Auswirkungen auf den Wnt- und Hedgehog-Signalweg
  • Niclosamide concentrations as low as 3 µM resulted in significant reduction in the number of vital cells in all three pancreatic cancer cell lines. In human MIA PaCa-2 and Panc-1 even the lowest concentration (0.1 µM) had a significant inhibitory effect on the relative cell number (MIA PaCa-2 to 48 % and Panc-1 to 55 %); p?0.05. We were also able to demonstrate that niclosamide inhibited cell migration in MIA PaCa-2 to 28 % and Panc-1 to 27 % at a concentration of 0.5 µM when compared to the untreated control.
  • Niclosamide worked in at least three ways: it inhibited pancreatic cancer cell prolifera¬tion and migration, it promoted cell necrosis and apoptosis, and it caused a G0/G1 cell cycle arrest. Using real time PCR, we also showed the ability of niclosamide to modulate the canonical Wnt-pathway, which is known to be one major signaling pathway involved in pancreatic tumorgenesis.
  • ediss.uni-goettingen.de/handle/11858/00-1735-0000-0028-86A3-C?locale-attribute=en

Oridonin

  • Extracted from the Chinese herb Rabdosia rubescens
  • Is a natural compound with the structure of a tetracycline diter-penoid
  • Exert antitumor effects and is widely used
  • Oridonin effectively induced cell apoptosis of pancreatic cancer cells
  • Nanosuspension was more effective than free oridonin on
    • G2/M-phase cell cycle arrest
    • Apoptosis in the PANC-1 human pancreatic cancer cell line
  • Induces apoptosis and senescence
    • By increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells
  • Autophagy preceded apoptosis in oridonin-treated MCF-7 human breast cancer cells
  • In lung cancer patients, oridonin also suppressed
    • Mammalian target of rapamycin (mTOR) signaling
    • Supesed growth of lung cancer tumors
      • Inhibition of mTORC1 may be an effective target
  • www.spandidos-publications.com/10.3892/mmr.2016.4897

Oxaliplatin



Paclitaxel

Týdenní podávání - weekly metronomic schedule

    • May also have activity in pancreatic cancer
    • Encouraging results + nab-paclitaxel and cationic liposomal paclitaxel in combination with gemcitabine [6]
    • Paclitaxel to be more effective than the previous standard doses of this agent given every 3 weeks in the neoadjuvant, adjuvant and metastatic settings in breast cancer, with a similar benefit seen in ovarian cancer [6]
  • May facilitate increased efficacy of the other chemotherapy agents
      • Oxaliplatin
      • 5-FU
    • Allowing the agents to reach the tumor better
    • Lower doses of chemotherapy to be used to attain equal or higher concentrations of the chemotherapy in the tumor bed [6]
    • Allowing fewer side effects systemically [6]

RAGE-silencing by shRNA

  • Diminished autophagy
  • Increased apoptotic rate
  • Decreased tumor cell survival in human panc and mouse panc02 cancer cell lines [18]

RNA interference targeting glutaminase

  • Significant reduction in PDAC cell growth
  • Targeting of transaminase
    • Abolishes the noncanonical pathway in which PDAC cells metabolize glutamine [18]

Salirasib (Ras inhibitor)

  • Significant antiproliferative effects in pancreatic cancerous cells
    • Panc-1 and MIA PaCa-2
    • Melanoma, Merkel cell carcinoma, LNCaP, CWR-R1
  • Reduction of Ras-mediated downstream signaling pathway
    • Including Akt and Erk
  • Antiproliferative effects in glioblastoma cells
    • Apoptotic cell death
    • HIF-1? degradation
      • Glycolysis shutdown
      • Severe energy crisis [18]

Salirasib + 2-DG (glucose analog)

  • Additive inhibition of cell proliferation
  • Synergistic induction of apoptosis
  • Complete shrinkage of Panc-1 pancreatic carcinoma cells
  • Glycolysis inhibition [18]

S. typhimurium A1-R

  • Promising effect on disseminated ovarian cancer
    • Especially after intraperitoneal administration in nude mouse models [8]
  • A significant effect of the A1-R strain against pancreatic cancer has been described in different mouse models
    • Nude, C57BL/6 and C57BL/6 CD8-/- (B6.129S2-CD8atm1Mak/J mice)
  • Clinical implications have been described [8]

Terapie bolesti

  • Analgetika
  • Radioterapie
    • Vysokoenergetické záření může snížit bolest zmenšením nádoru
  • Nervová blokáda
    • Injekce alkoholu do oblasti kolem určitých nervů v břiše může přerušit přenos bolesti
  • Chirurgický výkon
    • Přerušit určité nervy a tím zablokovat přenos bolesti

Výživa a terapie podvýživy

  • Trpí často nechutenstvím vlivem chemoterapie, nádoru samotného
  • Dostatek kalorií a bílkovin k zabránění váhového úbytku
  • Léky nahrazující enzymy a hormony, které se tvoří ve slinivce

Salinomycin: a antibiotic that has been shown to target cancer stem cells in preclinical studies of pancreatic cancer.
Metformin: a commonly used diabetes medication that has been shown to have anti-cancer properties and may target cancer stem cells in pancreatic cancer.
Gamitrinib: a small molecule inhibitor of the protein Bcl-xL, which is involved in the survival of cancer cells. Gamitrinib has been shown to induce ferroptosis in pancreatic cancer cells in preclinical studies.
Elesclomol: a small molecule that has been shown to induce ferroptosis in pancreatic cancer cells in preclinical studies.
Quercetin: a plant flavonoid with potential anti-cancer properties. Quercetin has been shown to target cancer stem cells and induce ferroptosis in pancreatic cancer cells in preclinical studies.Paclitaxel: a chemotherapy drug that is commonly used to treat pancreatic cancer. Paclitaxel has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells.
Gemcitabine: a chemotherapy drug that is commonly used to treat pancreatic cancer. Gemcitabine has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells.
5-FU: a chemotherapy drug that is sometimes used to treat pancreatic cancer. 5-FU has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells.
ABT-263: a small molecule inhibitor of the protein Bcl-2, which is involved in the survival of cancer cells. ABT-263 has been shown to induce ferroptosis in pancreatic cancer cells in preclinical studies.
Erastin: a small molecule that has been shown to induce ferroptosis in pancreatic cancer cells in preclinical studies.Selumetinib: a small molecule inhibitor of the protein MEK, which is involved in the MAPK signaling pathway. Selumetinib has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
GSK343: a small molecule inhibitor of the protein Notch, which is involved in the development and maintenance of cancer stem cells. GSK343 has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Vorinostat: a small molecule inhibitor of the protein HDAC, which is involved in the regulation of gene expression. Vorinostat has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
GDC-0919: a small molecule inhibitor of the protein PI3K, which is involved in the regulation of cell growth and survival. GDC-0919 has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.Plumbagin: a plant-derived compound with potential anti-cancer properties. Plumbagin has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Curcumin: a compound found in the spice turmeric with potential anti-cancer properties. Curcumin has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Honokiol: a compound found in the bark of the magnolia tree with potential anti-cancer properties. Honokiol has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Pterostilbene: a compound found in blueberries with potential anti-cancer properties. Pterostilbene has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Genistein: a compound found in soybeans with potential anti-cancer properties. Genistein has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.ABT-263: a small molecule inhibitor of the protein Bcl-2, which is involved in the survival of cancer cells. ABT-263 has been shown to induce ferroptosis in pancreatic cancer cells in preclinical studies.
Erastin: a small molecule that has been shown to induce ferroptosis in pancreatic cancer cells in preclinical studies.Epigallocatechin gallate (EGCG): a compound found in green tea with potential anti-cancer properties. EGCG has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Resveratrol: a compound found in grapes and red wine with potential anti-cancer properties. Resveratrol has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Quercetin: a plant flavonoid with potential anti-cancer properties. Quercetin has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Erythrodiol: a compound found in olive oil with potential anti-cancer properties. Erythrodiol has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.
Apigenin: a compound found in various plants with potential anti-cancer properties. Apigenin has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.Silvestrol: a compound found in the bark of the Annonaceous acetogenins plant family with potential anti-cancer properties. Silvestrol has been shown to target cancer stem cells and inhibit their proliferation in pancreatic cancer cells in preclinical studies.

Zyflamend

  • Supercritical fluid (CO2)
  • Hydroalcoholic extracts of the herbs:
    • Rosemary (Rosmarinus officinalis L.).
    • Turmeric (Curcuma longa L.).
    • Ginger (Zingiber officinale Roscoe).
    • Holy basil (Ocimum sanctum L.).
    • Green tea (Camellia sinensis [L.] Kuntze).
    • Hu zhang (Polygonum cuspidatum Siebold & Zucc.).
    • Chinese goldthread (Coptis chinensis Franch.).
    • Barberry (Berberis vulgaris L.).
    • Oregano (Origanum vulgare L.).
    • Baikal skullcap (Scutellaria baicalensis Georgi).
  • 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]
  • COXs are enzymes that convert arachidonic acid into prostaglandins, which are thought to play a role in tumor development and metastasis
    • COX-2, is activated during chronic disease states, such as cancer
  • Zyflamend may suppress activation of nuclear factor-kappa B (NF-kappa B)
  • Lipoxygenase isozymes 5-LOX and 12-LOX
  • 0.25 µL/mL to 2 µL/mL of Zyflamend produced decreases in 5-LOX and 12-LOX expression in PC3 prostate cancer cells
    • Inhibited cell proliferation and induced apoptosis
    • Decrease in Rb phosphorylation (Rb proteins control cell-cycle-related genes)
  • 200 µg/mL
    • After 48 hours of treatment, a statistically significant reduction in cell growth was observed for Zyflamend-treated cells
  • Insulin-like growth factor-1 (IGF-1; 0–100 ng/mL) alone or in combination with Zyflamend (200 µg/mL)
    • IGF-1 alone exhibited statistically significant, dose-dependent increases in cell proliferation
    • IGF-1 and Zyflamend showed significant decreases in cell proliferation
  • Zyflamend
    • Inhibits the expression of class I and class II histone deacetylases (HDAC)
    • Upregulated their downstream target p21 suppressor gene
    • Chinese goldthread and baikal skullcap appeared to be the most likely major contributors to the overall Zyflamend effect on HDAC expression.
  • Human colorectal carcinoma cell lines in vitro with Zyflamend
    • Significantly down regulate expression of antiapoptotic proteins
    • Up regulate expression of Bax (a proapoptotic protein)
    • Increase expression of death receptor 5 (DR5)
  • Nude mice with pancreatic cancer cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks
    • Tumor cells from the Zyflamend-treated mice showed significant reductions in antiapoptotic proteins
    • Significantly increased expression of DR5
  • Nude mice with pancreatic cancer cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks
    • Tumor cells from the Zyflamend-treated mice showed significant reductions in antiapoptotic proteins
    • Significantly increased expression of DR5
  • 2011 study, mice were also implanted with pancreatic cancer cells
    • Gemcitabine and/or Zyflamend
    • Combination treatment resulted in a significantly greater decrease in tumor growth than did treatment with gemcitabine or Zyflamend alone
    • Zyflamend exerted its effects by sensitizing the pancreatic tumors to gemcitabine
      • Through suppression of multiple targets linked to tumorigenesis

www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq

O úroveň výše

Poslední aktualizace: 10. 12. 2023 21:56:33