Dietary Polyunsaturated Fatty Acids: Impact on Cancer Chemotherapy and Radiation

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:   Frankp@chiro.org

Alternative Medicine Review 2002 (Feb);   7 (1):   4–21 ~ FULL TEXT

Kenneth A. Conklin, MD, PhD


Introduction

Interpreting Reactive Oxygen Species (ROS) Mediated Mechanisms

Interpreting the results of studies designed to assess the impact of polyunsaturated fatty acids (PUFAs) on chemotherapy and radiation is difficult because PUFAs alone can affect cancer cell growth and viability. PUFAs create oxidative stress (Table 1) in biological systems as they undergo lipid peroxidation, forming free radicals such as peroxyl and alkoxyl radicals. Although these lipid hydroperoxides are relatively short-lived, their breakdown results in the formation of secondary products of lipid peroxidation (aldehydes such as malondialdehyde and the 4-hydroxyalkenals) that are longer-lived and can attack a variety of cellular targets.

Low concentrations of these aldehydes affect the cell cycle (Figure 1) in ways that reduce the rate of cell proliferation. These effects include inhibiting the transition of cells from the G0 phase to the G1 phase, prolonging the G1 phase, slowing progression through the S phase by inhibiting the activity of DNA polymerases, inhibiting cell cycle progression through the restriction point, and causing arrest at cycle cell checkpoints. [1,2] These effects that retard cell cycle progression will impact proliferating cells such as those in culture and those of certain animal tissues, including neoplasms, bone marrow, and the intestinal epithelium. Whereas low-level PUFA-induced oxidative stress is cytostatic, higher levels of oxidative stress result in apoptosis (programmed cell death), and still higher levels cause cellular necrosis. [3-5]

Many investigators have demonstrated that omega-6 (n-6) and omega-3 (n-3) PUFAs ­ including linoleic acid (LA), gamma-linolenic acid (GLA), dihommogamma-linolenic acid (DGLA), arachidonic acid (AA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) ­ inhibit growth and are cytotoxic to cancer cells in vitro; [6-15] that the effects are associated with the production of lipid peroxides and aldehydes; [8-13] and that the cytotoxicity of the added PUFAs is reduced by the addition of antioxidants. [8-13] Studies with laboratory animals have also demonstrated that feeding a diet containing peroxidation products of fish oil1 [6] reduces tumor growth, and that the effect is reduced by administering antioxidants. [17,18]

However, the effects in vitro are observed at PUFA concentrations (30 microM and above in most studies) exceeding normal plasma free fatty acid (FFA) levels. PUFAs in culture medium undergo lipid peroxidation more readily than those of plasma or tissues because: (1) culture medium, compared to plasma, contains lower levels of albumin that binds FFAs [19] and sequesters iron and copper that promote lipid peroxidation; (2) culture medium generally contains fewer antioxidants than plasma; (3) PUFAs in plasma lipoproteins are protected by antioxidants within the lipoproteins; and (4) cellular PUFAs are protected from lipid peroxidation by multiple antioxidants. Additionally, growth inhibition in vitro does not necessarily correlate with the degree of lipid peroxidation [13] and antioxidants preventing lipid peroxidation in vitro do not completely reverse the effects of certain PUFAs on cell growth. [11,12,14]

Researchers found that administering LA without antioxidants also reverses the suppressive effects of fish oil on the growth of colon adenocarcinoma in mice. [20] Further research has found that preventing lipid peroxidation in experimental diets by the addition of antioxidants does not interfere with the growth inhibitory effects of fish oil on primary tumor growth or the development of metastases in nude mice with transplanted human breast and prostate cancer cells. [21-23] These results suggest PUFAs are cytostatic and cytotoxic in vitro and in vivo when conditions allow lipid peroxidation to occur, but that certain PUFAs in the absence of oxidative stress also have inhibitory effects on tumor cell growth.

Return to the CANCER & EFAs Page

Return to the OMEGA-3 FATTY ACIDS Page

Since 3-01-2002