nemoci-sympt/ONKOLOGIE/nadory-pankreatu/nadory-slinivky-maligni/terapie-podpurne-kroky

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]

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

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]

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

• Benefit of cca 11 months versus about 6.5 months for gemcitabine alone [4]
• www.texasoncology.com/types-of-cancer/pancreatic-cancer/stage-iv-pancreatic-cancer/

Gemcitabine + Abraxane

• 8.5 versus 6.5 months for gemcitabine [4]
• www.texasoncology.com/types-of-cancer/pancreatic-cancer/stage-iv-pancreatic-cancer/

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.

Leucovorin/5-FU

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:
• Mitogen-activated protein kinase scaffold protein 1 (MP1) [21]
• P14
• P18 trimeric proteins [21]
• 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
• Transported into the mitochondrial matrix via translocase
• 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:
• Fatty acid synthesis
• cholesterol synthesis [21]
• Decreases the activities of:
• 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR)
• Synthesizes isoprenoids and cholesterol
• Acyl coenzyme A:cholesterol acyltransferase (ACAT)
• Endoplasmic reticulum protein
• Catalyzes the formation of cholesterol esters from:
• Acyl-CoA
• cholesterol
• 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:
• An inhibitor of cholesterol synthesis
• And metformin [21]
• 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]

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

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