Dietary menhaden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX‐1

Abstract

In the present study, we investigated the effects of high levels of dietary fish oil on the growth of MX-1 human mammary carcinoma and its response to mitomycin C (MC) treatment in athymic mice. We found that high levels of dietary fish oil (20% menhaden oil + 5% corn oil, w/w) compared to a control diet (5% corn oil, w/w) not only lowered the tumor growth rate, but also increased the tumor response to MC treatment. We also found that high levels of dietary fish oil significantly increased the activities of tumor xanthine oxidase and DT-diaphorase, which are proposed to be involved in the bioreductive activation of MC. Since menhaden oil is highly unsaturated, its intake caused a significant increase in the degree of fatty acid unsaturation in tumor membrane phospholipids. This alteration in tumor membrane phospholipids made the tumor more susceptible to oxidative stress, as indicated by the increased levels of both endogenous lipid peroxidation and protein oxidation after feeding the host animals the menhaden oil diet. In addition, the tumor antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPOx), and glutathione S-transferase peroxidase (GSTPx), were all significantly enhanced by feeding a diet high in fish oil. MC treatment caused further increases in tumor lipid peroxidation and protein oxidation, as well as in the activities of CAT, SOD, GPOx, and GSTPx, suggesting that MC causes oxidative stress in this tumor model which is exacerbated by feeding a diet high in menhaden oil. Thus, feeding a diet rich in menhaden oil decreased the growth of human mammary carcinoma MX-1, increased its responsiveness to MC, and increased its susceptibility to endogenous and MC-induced oxidative stress, and increased the tumor activities of two enzymes proposed to be involved in the bioactivation of MC, that is, DT-diaphorase and xanthine oxidase. These findings support a role of these two enzymes in the bioactivating of MC and indicate that the type of dietary fat may be important in tumor response to therapy.

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

“…However, there have been few investigations of the potential use of inducers of DT-diaphorase to enhance the anti-tumour activity of anti-tumour agents that are activated by this enzyme. Shao et al (1995) found that the fish oil menhaden oil increased DT-diaphorase activity in an MX-1, human mammary carcinoma, tumour grown in athymic mice and also increased the response of the tumour xenograft to MMC. We have shown that D3T, an inducer of DT-diaphorase, can increase the level of DT-diaphorase activity in murine lymphoma cells without altering the level of enzyme activity in normal murine marrow cells, resulting in an increase in the anti-tumour activities of MMC and E09 (Begleiter et al, 1996).…”

“…A study by Shao et al (1995) found that high levels of dietary fish oil lowered the growth rate of MX-1, human mammary carcinoma, xenografts in athymic mice and increased DT-diaphorase activity in the tumour. The high levels of fish oil also increased the response of the tumour to MMC.…”

Consumption of an omega-3 fatty acids product, INCELL AAFA™, reduced side-effects of CPT-11 (irinotecan) 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. The results of in vitro studies have shown that a small amount of either eicosapentaenoic acid (EPA) or of docosahexaenoic acid (DHA), the major long chain polyunsaturated fatty acids (PUFAs) found in fish oil, added to cell culture media can cause tumour cell death but not kill cultured normal cells (de Vries and Van Noorden, 1992).…”

Recent Highlights in the Development of Isatin-Based Anticancer Agents

“…In this study, EPA was found to significantly increase the cytotoxicity of isatin towards MDA-MB-231 cells in vitro via modulation of lipid peroxidation. Omega-3 fatty acids have previously been shown to increase the efficacy of various cancer chemotherapy drugs such as doxorubicin [178][179], tamoxifen [180], and mitomycin C [181], as well as radiation therapy [182]. Table 1).…”