Omega-3 fatty acids and cancer therapy W. Elaine Hardman, Ph.D. Department of Biochemistry and Microbiology Marshall University School of Medicine Huntington, West Virginia
<ul><li>Outline </li></ul><ul><li>What are omega 3 fatty acids? </li></ul><ul><li>Pre-clinical evidence for benefit of n-3 fatty acids during cancer therapy </li></ul><ul><li>Potential mechanisms for therapeutic benefit of n-3 fatty acids </li></ul><ul><li>Clinical evidence for benefit of n-3 fatty acids during cancer therapy </li></ul>
Major fat types Stearic 18:0 5 3 7 9 11 13 15 17 Saturated fat Monounsaturated fat OH C 12 9 18 16 O Oleic (OA) 18:1n-9 C O OH
Linoleic (LA) 18:2n-6 O 18 C 13 12 9 OH OH C 12 9 O 18 15 Linolenic (LNA) 18:3n-3 Polyunsaturated fats
Pre-clinical evidence for benefit of omega-3 fatty acids during cancer therapy Supplementing the diet with omega-3 fatty acids may suppress the growth of existing cancers and may prevent or slow metastasis Omega 3 fatty acids may increase the efficacy of chemo- or radiation therapy
Hormone responsive tumors such as: breast, prostate and colon cancers seem especially sensitive to omega 3 fatty acids. However, in animal models, lung cancer growth has been also slowed by omega 3 fatty acids.
In animal models, the efficacies of: epirubicin (Bougnoux), 5-fluorouracil (Hochwald), mitomycin C (Pardini), araC (Cha) and tamoxifen (DeGraffenried) have also been enhanced in the presence of an omega 3 dietary supplement.
Omega 3 fat may increase radiation sensitivity of cancer cells Irradiation reduced the size of chemically induced rat mammary gland tumors (Colas, et al).
Metaphase index in MDA-231 tumors of mice fed omega 6 or omega 3 diets with or without gamma irradiation
Omega 3 fatty acids may reduce cancer cachexia Cachexia – from Greek kachexia - bad condition General physical wasting and malnutrition Usually associated with increasing tumor mass. Cannot be corrected by increasing food intake
Free radicals O 2 - Superoxide Hydroxyl HO Hydroperoxyl HO 2 Hydrogen peroxide H 2 O 2 Lipid peroxide LO 2 H Reactive nitrogen species Thiyl
Membranes Mitochondria Enzymes Chromosomes DNA Scientific American, Dec. 1992
Defenses from oxidative damage Endogenous antioxidative enzymes: Superoxide dismutase Catalase Glutathione peroxidase Exogenous antioxidants: Vitamin E and beta carotenes Uric acid and Vitamin C Metal chelators
How could the efficacy of chemotherapy be altered without causing additional damage to normal cells? <ul><li>Most chemotherapeutic drugs cause oxidative damage to cells. </li></ul><ul><li>Fat composition of all tissues can be altered by changing the fats content of the diet. </li></ul><ul><li>Activity of endogenous antioxidative enzymes can be altered in cells. </li></ul>
Antioxidant enzyme activity in mice fed 5% CO or 3% FOC/2% CO diets with or without DOX treatment for 2 wks
DHA inhibits eicosanoid synthesis from AA (Rose and Connolly, 1999) EPA effectively out-competes AA for COX activity (Needleman, P., 1979; Yang, P., et al., 2002) EPA is a better substrate for COX 2 than AA . (Yang, P., et al., 2002)
Residual cancer cells must multiply for the tumor to reoccur or for metastatic sites to grow LA and AA activate PKC stimulating mitosis (Hannun et al., 1986) N-3 fatty acids decrease activity of ras (Collett et al, 2001) and AP-1 (Liu, et al., 2001) AA products of COX and LOX increase mitosis; EPA and DHA decreased mitosis and inhibited growth of breast and colon cancer cells (Rose & Connolly, 1990; Buckman, 1991; Abou-El-Ela, 1989)
Functional apoptotic pathways help control cell growth COX-2 expression downregulates apoptotic pathway (Tsujii & DuBois, 1995, Connolly & Rose, 1998) NF B activation blocks apoptosis (Schwartz, 1999), n-3 fatty acids block NF B activation DHA inactivated Bcl-2 family genes and increased transcription of genes and transcription factors that induce apoptosis (Narayanan, et al, 2001; Chiu, et al., 1999)
Terminally differentiated cells don’t multiply Omega -3 fatty acids induced differentiation of breast cancer cells (Wang, 2000)
Angiogenesis must occur for tumors to grow and metastasize n-6 products of COX-2 and 12-LOX stimulate angiogenesis, n-3 products do not (Form & Auerback, 1983; Connolly & Rose, 1998)
Omega 3 fatty acids decrease estrogen metabolism PGE 2 activates P450 aromatase to increase estrogen production (Noble, et al. 1997) Shift in estrogen metabolism towards 16 -hydroxylation increases the formation of aberrant hyperproliferation in breast. Omega-3 supplements decreased 16 -hydroxylation (Osborne, et al. 1988)
<ul><li>Summary: </li></ul><ul><li>N-3 fatty acids may be detrimental to growth of metastatic or residual cancer cells by: </li></ul><ul><li>Altering eicosanoid metabolism </li></ul><ul><li>Slowing cancer cell mitosis </li></ul><ul><li>Increasing cancer cell death </li></ul><ul><li>Inducing differentiation </li></ul><ul><li>Suppressing angiogenesis </li></ul><ul><li>Altering estrogen metabolism </li></ul>
Maximum tolerated dose Burns, et al. Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukemia group B study 9473. Clin Cancer Res. 5:3842, 1999 Univ. of Iowa Cancer Center 0.3 g/kg/day - 70 kg patient can consume up to 21 g/day Dose limiting toxicity was gastrointestinal, mainly diarrhea
<ul><li>Effects on cachexia </li></ul><ul><li>Barber, Fearon, Tisdale (Dept of Surgery, Univ of Edinburgh) </li></ul><ul><li>Various papers on cachexia in pancreatic cancer patients </li></ul><ul><li>EPA supplement improved life span in pancreatic cancer patients even with no other treatment </li></ul><ul><li>Patients consuming an n-3 containing supplement gained weight and quality of life was improved </li></ul><ul><li>Patients excreted less IL-6 and less proteolysis inducing factor </li></ul>
Breast cancer Bougnoux (Univ Tours) –localized breast carcinoma patients with higher levels of DHA in breast adipose tissue responded better to chemotherapy. Level of n-3 fatty acids was higher in patients with complete or partial remission than in patients with no response or tumor progression (p < 0.004) Bagga (UCLA School of Medicine) – consumption of an n-3 supplement for 3 months significantly changed composition of breast adipose tissue. Breast adipose composition changed more rapidly than gluteal adipose composition.
Epidemiology studies Simonsen et al. Am J Epidemiology 147:342, 1998 4 of 5 centers n3/n6 EURAMIC = breast cancer risk Goodstein et al. J Nutr 133:1409, 2003 Premenopausal n3/n6 = non significant breast cancer risk Postmenopausal n3/n6 = significant breast cancer risk Maillard et al. Int J Cancer 98:78, 2002 DHA = significant breast cancer risk long chain n3/n6 = significant breast cancer risk Bagga et al. Nutr Cancer 42:180, 2002 N6 fat significantly higher in breast cancer cases for a given level of n6, higher EPA or DHA were protective Pala et al J Natl Cancer Inst 93:1088, 2001 DHA = significant breast cancer risk
<ul><li>Summary </li></ul><ul><li>Preclinical studies indicate that n-3 fatty acids should be beneficial for cancer treatment </li></ul><ul><li>Mechanistic studies indicate feasible mechanisms for the influence of n-3 fatty acids on tumor growth, survival and response to chemotherapy </li></ul><ul><li>Limited clinical studies that are available indicate that n-3 fatty acids have been beneficial during cancer therapy or may reduce risk for breast cancer </li></ul>