Alpha-linolenic acid regulates the growth of breast and cervical cancer cell lines through regulation of NO release and induction of lipid peroxidation

Rashmi Deshpande, Prakash Mansara, Snehal Suryavanshi, Ruchika Kaul-Ghanekar

Abstract


In the present work, we have analyzed the effect of the essential fatty acid, alpha linolenic acid (ALA) on nitric oxide release as well as induction of lipid peroxidation in breast (MCF-7 and MDA-MB-231) and cervical (SiHa and HeLa) cancer cell lines. ALA-treated cells showed a dose-dependent decrease in cell viability in both breast and cervical cancer cell lines without affecting the viability of non-cancerous transformed HEK 293 cells. Both types of cancer cells treated with ALA demonstrated a significant reduction in nitric oxide (NO) release with a simultaneous increase in lipid peroxidation (LPO). This was followed by a decrease in the mitochondrial membrane potential as well as activation of caspase 3 leading to apoptosis. Thus, ALA regulated the growth of cancer cell lines through induction of lipid peroxidation and modulation of nitric oxide release resulting in apoptosis.


Keywords


Alpha Linolenic acid; ALA; Nitric Oxide; NO; Lipid peroxidation; LPO

References


Allayee H, Roth N & Hodis HN 2009 Polyunsaturated fatty acids and cardiovascular disease: implications for nutrigenetics. J Nutrigenet Nutrigenom 2 140-148.

Araki Y, Matsumiya M, Matsuura T, Oishi M, Kaibori M, Okumura T, Nishizawa M, Takada H & Kwon AH 2011 Peroxidation of n-3 polyunsaturated fatty acids inhibits the induction of iNOS gene expression in proinflammatory cytokine-stimulated hepatocytes. J Nut Metab 2011 374542.

Barceló-Coblijn G & Murphy EJ 2009 Alpha-linolenic acid and its conversion to longer chain n-3 fatty acids: benefits for human health and a role in maintaining tissue n-3 fatty acid levels. Prog Lipid Res 48 355-374.

Bougnoux P, Hajjaji N, Maheo K, Couet C & Chevalier S 2010 Fatty acids and breast cancer: Sensitization to treatments and prevention of metastatic re-growth. Prog Lipid Res 49 76-86.

Burdge GC & Calder PC 2005 Conversion of α-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod Nutr Dev 45 581-597.

Cao XH, Wang AH, Wang CL, Mao DZ, Lu MF, Cui YQ & Jiao RZ 2010 Surfactin induces apoptosis in human breast cancer MCF-7 cells through a ROS/JNK-mediated mitochondrial/caspase pathway. Chemico-Biol Inter 183 357-362.

Cauwels A, Bultinck J & Brouckaert P 2005 Dual role of endogenous nitric oxide in tumor necrosis factor shock: induced NO tempers oxidative stress. Cell Mol Life Sci 62 1632-1640.

Crowell JA, Steele VE, Sigman CC & Fay JR 2003 Is inducible nitric oxide synthase a target for chemoprevention? Mol Cancer Ther 2 815-823.

Das UN 1999 Essential fatty acids, lipid peroxidation and apoptosis. Prostaglandins Leukot Essent Fatty Acids 61 157-163.

Das UN 2000 Interaction(s) between nutrients, essential fatty acids, eicosanoids, free radicals, nitric oxide, anti-oxidants and endothelium and their relationship to human essential hypertension. Med Sci Res 28 75.

Das UN 2002 A radical approach to cancer. Med Sci Monit 8 RA 79-92.

Das UN, Madhavi N, Sravan Kumar G, Padma M & Sangeetha P 1998 Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites? Prostaglandins Leukot Essent Fatty Acids 58 39-54.

De Stefani E, Deneo-Pellegrini H, Mendilaharsu M & Ronco A 1998 Essential fatty acids and breast cancer: a case±control study in Uruguay. Int J Cancer 76 491-494.

Ding WQ, Liu B, Vaught JL, Palmiter RD & Lind SE 2006 Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells. Mol Cancer Ther 5 1864-72.

Franceschi S, Favero A, Decarli A, Negri E, La Vecchia C, Ferraroni M, Russo A, Salvini S, Amadori D, Conti E, Montella M & Giacosa A 1996 Intake of macronutrients and risk of breast cancer. Lancet 347 1351-1356.

Fritsche KL & Johnston PV 1990 Effect of dietary alpha-linolenic acid on growth, metastasis, fatty acid profile and prostaglandin production of two murine mammary adenocarcinomas. J Nutr 120 1601-1609.

Gago-Dominguez M, Castelao JE, Pike MC, Sevanian A & Haile RW 2005 Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer. Cancer Epidemiol Biom Prev 14 2829-2839.

Gago-Dominguez M, Jiang X & Castelao JE 2007 Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis. Breast Cancer Res 9 201.

Hirose M, Masuda A, Ito N, Kamano K & Okuyama H 1990 Effects of dietary perilla oil, soybean oil and sa‚ower oil on 7,12-dimethyl-benz (a) anthracene (DMBA) and 1,2-dimethylhydrazine (DMH)-induced mammary gland and colon carcinogenesis in female SD rats. Carcinogenesis 11 731-735.

Hofseth LJ 2008 Nitric oxide as a target of complementary and alternative medicines to prevent and treat inflammation and cancer. Cancer Lett 268 10-30.

Hogg N & Kalyanaraman B 1999 Nitric oxide and lipid peroxidation. Biochim Biophys Acta Bioenerg 1411 378-384.

Horia E & Watkins BA 2005 Comparison of stearidonic acid and a-linolenic acid on PGE2 production and COX-2 protein levels in MDA-MB-231 breast cancer cell cultures. J Nutr Biochem 16 184-192.

Kamano K, Okuyama H, Konishi R & Nagasawa H 1989 Effects of a high-linoleate and high-alpha-linolenate diet on spontaneous mammary tumorigenesis in mice. Anticancer Res 9 1903-1908.

Kim BC, Kim HG, Lee SA, Lim S, Park EH, Kim SJ & Lim CJ 2005 Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. Biochem Pharmacol 70 1398-1407.

Kim JY, Park HD, Park E, Chon JW & Park YK 2009 Growth-inhibitory and proapoptotic effects of alpha-linolenic acid on estrogen-positive breast cancer cells. Ann N Y Acad Sci 1171 190-195.

Kim YM, Talanian RV & Billiar TR 2003 Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J Biol Chem 272 31138-31148.

Klein V, Chajès V, Germain E, Schulgen G, Pinault M, Malvy D, Lefrancq T, Fignon A, Le Floch O, Lhuillery C & Bougnoux P 2000 Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer. Eur J Cancer 36 335-340.

Krishna Mohan I & Das UN 2001 Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids. Nutrition 17 126-151.

Laight DW, Kaw AV, Carrier MJ & Anggård EE 1998 Interaction between superoxide anion and nitric oxide in the regulation of vascular endothelial function. Brit J Pharmacol 124 238-244.

Lechner M, Lirk P & Rieder J 2005 Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Sem Cancer Biol 15 277-289.

Lee JH, Li YC, Ip SW, Hsu SC, Chang NW, Tang NY, Yu CS, Chou ST, Lin SS, Lino C, Yang JS & Chung JG 2008 The role of Ca2+ in baicalein-induced apoptosis in human breast MDA-MB-231 cancer cells through mitochondria and caspase-3-dependent pathway. Anticancer Res 28 1701-1712.

Maejima Y, Adachi S, Morikawa K, Ito H & Isobe M 2005 Nitric oxide inhibits myocardial apoptosis by preventing caspase-3 activity via S-nitrosylation. J Mol Cell Cardiol 38 163-174.

Mahadik SP, Shendarkar NS, Scheffer RE, Mukherjee S & Correnti EE 1996 Utilization of precursor essential fatty acids in culture by skin fibroblasts from schizophrenic patients and normal controls. Prostaglandins Leukot Essent Fatty Acids 55 65-70.

Mahidhara RS, Hoffman RA, Huang S, Wolf-Johnston A, Vodovotz Y, Simmons RL & Billiar TR 2008 Nitric oxide-mediated inhibition of caspase-dependent T lymphocyte proliferation. J Leukoc Biol 74 403-411.

Menedez JA, Barbacid M.del Mar, Montero S , Sevilla E, Escrich E, Solanas M, Cortes-Funes H & Colomer R 2001 Effect of gamma-linolenic acid and oleic acid on paclitaxel cytotoxicity in human breast cancer cells. Eur J Cancer 37 402-413.

Miles AM, Bohle DS, Glassbrenner PA, Hansert B, Wink DA & Grisham MB 1996 Modulation of superoxide-dependent oxidation and hydroxylation reactions by nitric oxide. J Biol Chem 271 40-47.

Munoz SF, Silva RA, Lamarque A, Guzman CA & Eynard AR 1995 Protective capability of dietary Zizyphus mistol seed oil, rich in 18/3, n-3, on the development of two murine mammary gland adenocarcinomas with high or low metastatic potential. Prostaglandins Leukot Essent Fatty Acids 53 135-138.

Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, Nakamura M & Kakudo K 2006 Nitric Oxide in Breast Cancer: Induction of Vascular Endothelial Growth Factor-C and Correlation with Metastasis and Poor Prognosis. Clin Cancer Res 12 1201-1207.

Narayanan BA, Narayanan NK, Simi B & Reddy BS 2003 Modulation of Inducible Nitric Oxide Synthase and Related Proinflammatory Genes by the Omega-3 Fatty Acid Docosahexaenoic Acid in Human Colon Cancer Cells. Cancer Res 63 972-979.

Ozgocmen S, Ozyurt H, Sogut S, Akyol O, Ardicoglu O & Yildizhan H 2006 Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns. Rheumatol Int 26 598-603.

Pardini RS 2006 Nutritional intervention with omega3 fatty acids enhances tumor response to anti-neoplasticagents. Chemico-Biol Inter 162 89-105.

Rahkola P, Mikkola TS, Ylikorkala O & Vaisanen-Tommiska M 2009 Association between high risk papillomavirus DNA and nitric oxide release in the human uterine cervix. Gynecol Oncol 114 323-326.

Ren J & Chung SH 2007 Anti-inflammatory effect of alpha-linolenic acid and its mode of action through the inhibition of nitric oxide production and inducible nitric oxide synthase gene expression via NF-kappaB and mitogen-activated protein kinase pathways. J Agricult Food Chem 55 5073-5080.

Sagar PS & Das UN 1995 Cytotoxic Action of cis-Unsaturated Fatty Acids on Human Cervical Carcinoma (HeLa) Cells In Vitro. Prostaglandins Leukot Essent Fatty Acids 53 287-299.

Sinclair AJ, Attar-Bashi NM & Li D 2002 what is the role of alpha-linolenic acid for mammals? Lipids 37 1113-23.

Singh R, Koppikar SJ, Paul P, Gilda S, Paradkar AR & Kaul-Ghanekar R 2009 Comparative analysis of cytotoxic effect of aqueous cinnamon extract from Cinnamomum zeylanicum bark with commercial cinnamaldehyde on various cell lines. Pharm Biol 47 1174-1179.

Stark AH, Crawford MA & Reifen R 2008 Update on alpha-linolenic acid. Nutr Rev 66 326-332.

Sun Z, Wang H, Ye S, Xiao S, Liu J, Wang W, Jiang D, Liu X & Wang J 2012 Beta-eleostearic acid induce apoptosis in T24 human bladder cancer cells through reactive oxygen species (ROS)-mediated pathway. Prostaglandins Other Lipid Mediat 99 1-8.

Udenigwe CC, Lu YL, Han CH, Hou WC & Aluko R E 2009 Flaxseed protein-derived peptide fractions: Antioxidant properties and inhibition of lipopolysaccharide-induced nitric oxide production in murine macrophages. Food Chem 116 277-284.

Wang Y, Huang L, Abdelrahim M, Cai Q, Truong A, Bick R, Poindexter B & Sheikh-Hamad D 2009 Stanniocalcin-1 suppresses superoxide generation in macrophages through induction of mitochondrial UCP2. J Leukoc Biol 86 981-988.

Wei L, Gravitt PE, Song H, Maldonado AM & Ozbun MA 2009 Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus-Infected Cells. Cancer Res 69 4878-4884.

Xu W, Liu LZ, Loizidou M, Ahmed M & Charles IG 2002 The role of nitric oxide in cancer. Cell Res 12 311-320.

Zhao G, Etherton TD, Martin KR, West SG, Gillies PJ & Kris-Etherton PM 2004 Dietary alpha-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women. J Nutr 134 2991-2997.

Zhou P, Qian L & Iadecola C 2005 Nitric oxide inhibits caspase activation and apoptotic morphology but does not rescue neuronal death. J Cereb Blood Flo Metab 25 348-357.


Full Text: PDF

Refbacks

  • There are currently no refbacks.


Copyright © 2021 Journal of Molecular Biochemistry