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A rational approach to helping cancer patients with natural therapies - Dr William Barnes MbChb Bsc (otago)<br>FACNEM
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Natural therapies and cancer A rational approach to helping cancer patients with natural therapies Dr William Barnes MbChbBsc (otago) FACNEM
Chemotherapy success in cancer • According to a recent analysis of 5 year surviaval rates in cancer patients following chemotherapy, oncology has done little to cure cancer . val • Chemotherapy as a stand alone treatment provided a 23% overall cure rate for adult solid tumours. Ref:The contribution of cytoxic chemotherapy to 5 year survival in adult malignancies, Morton. G.et al Clinical oncology (2004)16 ;549-
Inflammation and cancer • Why is inflammation so important in cancer ? Because it drives : • 1 mitosis • 2 metastasis • 3 angiogenesis
angiogenesis • The process of neovasclarisation is controlled in normal tissues by a sequence of endogenous polypeptides that are secreted during growth, healing and tissue renewal. • Neoplasms are able to synthesize or induce some of these polypeptides.In particular Vascular endothelial growth factor (VEGF) and angiopoietins (APNS)
Hypoxia • All tumours have relative hypoxia, tumours outgrow their blood supply once they form masses greater than 1-2mm • Tumours do not grow progressively unless they induce blood supply from the surrounding stroma.
Inflammation and cancer • How: • Induction of cytokines : • NF Kappa • TNF alpha • Cox • Interleukins IL 1 IL6 IL 8 • VEGF • NO
Angiogenesis and inflammation • Cytokines involved in induction of angiogenesis: • TNF alpha • Cox 2/ Lox • IL8 • NOS
Host derived factors Innate immune system cells such as macrophages (TAMS)produce cytokines : • NF Kappa , TNF alpha, NO, IL8. Fibroblasts: • Producing, Fibroblast growth factor(FGF-1 and FGF-2 or bFGF) of which bFGF is the most potent.
Source of drivers for angiogenesis Tumour derived factors: • VEGF, anti angiopoietins are produced by hypoxic tumours • bFGF, Cox ,Lox, are up regulated genetically and screted by many tumours.ie; Squamous produces high levels of Cox and Lox. Ca bowel is noted for Cox production • The tumour therefore can regulate its own rate of angiogenesis.
High Expression of HIFa is a predictor of outcome in pancreatic cancer • Hypoxic intrinsic factor ( HIF).is a signalling molecule that up regulates VEGF
Radiotherapy • There is clear evidence whilst radiotherapy is a powerful antimitotic it also creates inflammation and as such angiogenesis: • During radiotherapy tumours increase there angiogenic potential. • Combination of antiangiogenic agents and radiotherapy is more effective: • AnsiauxR, Baudeletet al Clin Cancer Res 200511:743-50 • Koukourakis MI et al anticancer Res 2001:21 4301-9
Chemotherapy • “ NF KAPPA is a resistance factor to Platinum based Antineoplastic Drugs – new aproaches focusing on inhibition of this factor could help to minimize or even eliminate resistance to platinum drugs” • Vilma Maldonado Laguns and Jorge Melendez-Zajgla. • Hindawi Publishing Corporation • Metal Based Drugs Vol 2008
Supporting the cancer patient A sensible program to provide support to the cancer patient should include treatments that suppress : • Angiogenesis • Mitosis • Metastatic spread Deal with all of these 3 factors and results will be much better
Nutritional substances • Overwhelming evidence exists in the literature showing that natural substances, in particular polyphenols, flavonoids, minerals and vitamins decrease, inflammation angiogenesis and metastasis by decreasing: • Cox ,Lox ,Nf kappa, IL1 ,IL8 ,TNF alpha, bFGF, VEGF .
Genistein sensitises lymphoma to CHOP • Vivo study : Diffuse large cell lymphoma which are notable for high expression of NK Kappa • High NF Kappa thought to increase the resistance of these cells to CHOP (cyclophosphamide, doxorubicin,vincristine, and prednisolone) • Genistein enhanced the growth inhibitory effects of the chemotherapy • Mol cancer ther 203Dec2(12):1361-8
Inhibition of cell growth and VEGF in ovarian cancer cells by flavonoids • In vitro study on OVCAR cells( ovarian Cancer) • Six flavonoids including: apigenin, luteolin, quercetin, genistein,and kaempferol were shown to inhibit cancer cell growth. • The rank of VEGF inhibition: • Genistein>kaempferol>apigenin>quercetin >luteolin>cysplatin. • Nutr cancer 2008:60(6):800-9
Tamoxifen in Oestrogen negative breast cancer • In vivo: • Realistic doses of Tamoxifen can suppress the growth of ER-negative breast cancer when combined with EGCG. • This is achieved by a decrease in mTOR ( a signalling molecule for angiogenesis) and EGF in the tumour • Br J Cancer 2008 Oct 7:99 (1056-63)
6-Gingerol inhibits angiogenesis • In vitro and In vivo study; • study using melanoma cell line: • Anti-angiogenic activity was noted in vitro by inhibiting endothelial response to VEGF and bFGF. • In Vivo reduced numbers of lung metastasis were noted in treated animals. • Biochem Biophys Res Commun 2005Sep23;335(2):300-8
Dose Ranges of Phytochemicals for angiogenesis inhibition Herb Cancer adjuvant dose 1000-2500mg 3x daily 1000-2500mg 3x daily 600-1000mg 3xdaily 500-1500mg 3x daily 2000mg 3x daily • Curcumin • Green Tea • Grape seed extract • quercetin with bromelian • Silibinin • S.M Sagar MD D Yance MH and R.K.Wong MD • Current oncology – vol 13, Number 3
Modified citrus Pectin( MCP) • MCP is a fractionated pectin obtained from the peel and pulp of citrus fruits • MCP is rich in galactosides giving it affinity for certain types of cancer cells. • These galactosides bind to the surface galectins on the cancer cells • This bind stops metastatic cells from clumping and as such adhering to endothelial cells and developing as metastasis • Dose for clinical use 6 -30gms
MCP Lead Chelator • MCP has been shown to chelate lead from children . • Trial involved children 5-12 with serum levels over 20micog/dL. • 15 gms 3x daily ..Dramatic reductions in serum lead were observed over one month . • This correlated with increases in urinary lead levels in 24 hr collections. • Altern ther health Med 2008 Jul-Aug ;14(6):18
Suppression of proinflammatory responses by MCP • 2006 study on effects of MCP on Macrophage function. • Investigations of LPS activated macrophages expression of iNOS and COX-2 was conducted in vitro. • MCP reduced iNOS ,COX-2, and NF Kappa expression significantly. • Biochem Pharmacol 2006 Oct 168): 1001-9
Oral MCP in breast carcinoma • MCP given orally inhibits tumour growth angiogenesis and metastasis.i • in vivo • Studies in an athymic mouse model showed statistically reduced tumour growth and metastasis in mice given oral MCP • J Natl Cancer Inst 202 Dec 18;94(24:1854-62)
MCP Cancer • MCP has been shown to reduce metastasis angiogenesis, and tumour growth in : • Colon , breast , melanoma, prostate, lung,in both primary and metastatic cancers.
Vit D deficiency in breast cancer • A Canadian study published in 2008 involving 512 women showed that 37.5% of women had Vit D lower than 50nmol/L at diagnosis. These women: * had more aggressive disease * were 93% more likely to develope metastasis *were 73% more likely to die than women with normal levels of vit D at diagnosis. In this country vit D deficiency particularly in the elderly may be an epidemic Medscape medical news 26/5/08
Vit D levels • Vit D hydroxycalciferol nmol/L (50-150) • Mild deficiency 25-50 nmol/L • Mod deficiency 12.5-25 nmol/L • Severe deficincy <12.5 nmol/L • “Aus and NZ” MJA, 182(6): 281-285 2005
ABCG2 : the key to cancer resistance in cancer stem cells • Multi-drug resistance remains one of the most common reasons for chemotherapy failure. • The membrane transporter proteinABCG2/BCRP1 has been shown to reduce the intracellular concentrations of chemotherapy drugs such as; ironotecan and doxorubicin. • ABCG2 may be represented in greater amounts in cancer stem cells.
ABCG2 cont • ABCG2 may underlie the ability of the cancer stem cell to start the regeneration of the tumour post chemotherapy. • Substances that inhibit ABCG2 may increase the chemosensitivity of cancer stem cells to chemotherapy and as such improve chemotherapy response; • An Y, Ongkeko WM, Expert Opin Drug Metab Toxicol Aug 27 2009
Combined effects of flavonoids on ABCG2 • “ the added effects of multiple flavonoids for breast cancer resistant protein (ABCG2) inhibition .... Provides a rationale for using “flavonoid cocktails” as a potential aproach for multidrug resistance reversal in cancer treatment” • Zhang. S. et al ,Pharm Res 2004 Jul;21(7):1263-73
ABC transporter ABCG2 is inhibited by Quercetin • “ 20 umol of Quercetin was found to be the strongest inhibitor of ABCG2 in an in vitro study in HEK293 cells.” • 20umol can be achieved with 100mg Quercetin • May need less if used in synergy with other flavonoids • Yoshikawa M, et al,J exp ther oncol 2004 Apr:4(1) :25-35