Effects of iron supplementation and ET-18-OCH3 on MDA-MB 231 breast carcinomas in nude mice consuming a fish oil diet

Abstract

Summary Lipid peroxidation products can be cytotoxic. Our objectives were (1) to use two pro-oxidants (iron and a pro-oxidative drug) to selectively increase lipid peroxidation in the implanted human breast tumours of mice consuming fish oil and (2) to kill the cancer cells without harming normal host tissues. The theoretical basis for selective cytotoxicity is that normal cells are better able to handle oxidative stress than cancer cells. Male athymic nude mice, consuming an AIN-76 diet, were injected s.c. with MDA-MB 231 human breast carcinoma cells. Three weeks later, all mice had palpable tumours, 3-10 mm in diameter, and diets were changed to modified AIN-76 diets containing 19% menhaden fish oil and 1% corn oil with or without supplemental 0.3% ferric citrate. After 2 weeks, half of the mice on each diet (19% fish oil with or without supplemental ferric citrate) were injected (three times per week for 2 weeks) with the ether-lipid drug edelfosine (ET-18-OCH3). The concentration of lipid peroxidation products in tumours (as measured by thiobarbituric acid-reactive substances, TBARS) was significantly increased by both ferric citrate and ET-18-OCH3. The TBARS in livers were not increased, nor was there evidence of other harmful side-effects to the host mice. The addition of iron enhanced tumour cell death whereas ET-1 8-OCH3 suppressed tumour cell mitosis. The use of iron supplementation combined with ET-18-OCH3 resulted in the slowest growth rate, lowest mitotic index, highest level of lipid peroxidation products and increased the cytotoxic index in tumours without detectable harm to the host. That iron supplementation increased tumour suppression beyond that expected from the increase in the concentration of TBARS in the tumour merits further investigation.

Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer

“…(c) The suppression in cancer growth is eliminated by antioxidants, and this elimination is proportional to the inhibition of lipid peroxidation products by antioxidants (18, 24-26, 28, 29, 33, 35, 36). (d) Although therapeutic mechanisms are not always relevant to etiology, marine n-3 fatty acids have been shown to enhance the cancer-killing effect of several chemotherapeutic drugs, and this is thought to be achieved through increased lipid peroxidation or lipid peroxidation -related mechanisms (37,(39)(40)(41)(42)(43)(44)(45). We also have supporting evidence in humans implicating the peroxidation products of marine n-3 fatty acids as the proximal anticarcinogens (46).…”

“…(b) This suppression in cancer growth is enhanced by pro-oxidants (iron and drugs that increase lipid peroxidation; refs. 24,29,[35][36][37][38]. (c) The suppression in cancer growth is eliminated by antioxidants, and this elimination is proportional to the inhibition of lipid peroxidation products by antioxidants (18, 24-26, 28, 29, 33, 35, 36).…”

Consumption of an omega-3 fatty acids product, INCELL AAFA™, reduced side-effects of CPT-11 (irinotecan) in mice

“…Thus 2% AAFA TM in the diet reduced the side effects of CPT-11 treatment in mice. We have reported that supplementing the diet of mice with fish oil increased the efficacy of edelfosine against MDA-MB 231 human breast cancer (Hardman et al, 1997), doxorubicin against A549 human lung cancer (Hardman et al, 2000) and CPT-11 against MCF-7 human breast cancer (Hardman et al, 1999a). Other investigators have found that supplementing the diet with omega-3 fatty acids increased the efficacy of: epirubicin against rat mammary tumours (Germain et al, 1999) and cyclophosphamide (Shao et al, 1997) or mitomycin (Shao et al, 1995) against MX-1 human mammary tumours.…”

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

“…Studies in cell culture and animal models have shown that DHA and eicosapentaenoic acid (20:5, n-3) inhibit tumorigenesis (15,16) and the growth of rodent tumors (17,18) and human breast cancer xenografts (19,20). Importantly, n-3 polyunsaturated fatty acids selectively inhibit tumor cell proliferation and are significantly less toxic towards normal cells (21,22). DHA increases lipid peroxidation within cells (23), and the anticancer effects of DHA are blocked by the antioxidant vitamin E, indicating that oxidation plays a role in DHA's mechanism of action.…”