Sensitization by Dietary Docosahexaenoic Acid of Rat Mammary Carcinoma to Anthracycline: A Role for Tumor Vascularization

Abstract

Purpose: To investigate whether dietary docosahexaenoic acid (DHA), a peroxidizable polyunsaturated N-3 fatty acids, sensitizes rat mammary tumors to anthracyclines and whether its action interferes with tumor vascularization, a critical determinant of tumor growth. Experimental Design: Female Sprague-Dawley rats were initiated by N-methylnitrosourea to develop mammary tumors and then assigned to a control group (n = 18), receiving a supplementation of palm oil, or to a DHA group (n = 54), supplemented with a microalgae-produced oil (DHASCO, 1.5 g/d). The DHA group was equally subdivided into three subgroups with addition of different amounts of a-tocopherol. Epirubicin was injected weekly during 6 weeks after the largest tumor reached 1.5 cm 2 , and subsequent changes in the tumor surface were evaluated. Tumor vascularization was assessed by power Doppler sonography before and during chemotherapy.Results: DHA and a-tocopherol were readily absorbed and incorporated into rat tissues. Epirubicin induced a 45% mammary tumor regression in the DHA-supplemented group, whereas no tumor regression was observed in the control group. In the DHA group, before chemotherapy was initiated, tumor vascular density was 43% lower than in the control group and remained lower during chemotherapy. Enhancement of epirubicin efficacy by DHA was abolished in a dosedependent manner by a-tocopherol, and the same trend was observed for DHA-induced reduction in tumor vascular density. Conclusions: Dietary DHA supplementation led to a reduction in tumor vascularization before the enhancement of any response to anthracyclines, suggesting that DHA chemosensitizes mammary tumors through an inhibition of the host vascular response to the tumor.

Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial

“…This trial is a logical extension of earlier studies carried out in rodents and shows that a defined food component, namely DHA, can turn malignant mammary tumours from resistant to sensitive to chemo- (Colas et al, 2006) or radiation therapy (Colas et al, 2004). Our data show for the first time that a dietary intervention targeted on DHA is a feasible approach that has potential to substantially increase survival in metastatic breast cancer patients treated with chemotherapy.…”

“…Using cultured breast cancer cell lines, it was reported that pre-enrichment of these cells with DHA enhanced their sensitivity to a variety of anti-cancer classes of drugs (Begin et al, 1986;Menendez et al, 2005;Wang et al, 2007) and more specifically to anthracyclines, an oxidative stressinducing anti-cancer drug with a quinone structure (Germain et al, 1998;Mahéo et al, 2005). Furthermore, a prolonged (several weeks) supplementation with DHA (fish oil or algae-derived DHA), initiated before and continued during chemotherapy, consistently increased the sensitivity of autochthonous mammary tumours to anti-cancer drugs (Shao et al, 1997;Hardman et al, 2001;Colas et al, 2005Colas et al, , 2006. Similar results have been observed with radiation therapy (Colas et al, 2004).…”

“…This indicates that dietary DHA can make mammary tumours more sensitive to anti-cancer agents. DHA-induced tumour chemosensitisation or radiosensitisation was abolished by the concomitant addition of a-tocopherol, an anti-oxidant molecule (Colas et al, 2004(Colas et al, , 2005 in a dose-dependent manner (Colas et al, 2006). With six double bonds, DHA is one of the most peroxidisable fatty acids and the increased sensitivity of tumour cells to chemotherapy may result in part from peroxidation of membrane-enriched DHA, as a consequence of the oxidative stress induced by anti-cancer drugs (Mahéo et al, 2005).…”

Interaction of ω-3 polyunsaturated fatty acids with radiation therapy in two different colorectal cancer cell lines

“…Both have been described to increase the therapeutic efficacy of RT in breast cancer cell lines, 8 rodent model 9 and also in patients. 10 In CRC, EPA or DHA, on its own, inhibits HT-29 cell growth, but DHA is more efficient than EPA due to its rapid cellular absorption and integration into cell membrane.…”

Lipid Rafts as Master Regulators of Breast Cancer Cell Function

“…These microdomains cluster together proteins involved in the regulation of crucial cellular processes; many of which are altered in cancer cells (Pike, 2003;de Laurentiis et al, 2007). Furthermore, lipid rafts are readily modified by diet and nutrition (Schley et al, 2007;Yaqoob, 2009), and studies have shown that fatty acid supplementation sensitises human mammary tumour cells to the cytotoxic effects of anti-cancer agents in vitro and in vivo (Germain et al, 1998;Menendez et al, 2005;Colas et al, 2006). This chapter will focus on the potential regulatory functions of lipid rafts as a novel approach towards understanding mechanisms of cancer initiation, progression and cell migration, a key event preceding metastatic progression.…”