Enhancement of arsenic trioxide‐mediated apoptosis using docosahexaenoic acid in arsenic trioxide‐resistant solid tumor cells

Abstract

It has been shown that the polyunsaturated fatty acid docosahexaenoic acid (DHA) can sensitize various tumor cells to reactive oxygen species (ROS)-inducing anticancer agents. Recently, we demonstrated that DHA also enhances the apoptotic effect of clinically achievable concentrations (1-2 M) of arsenic trioxide (As 2 O 3 ) in several As 2 O 3 -resistant human leukemic cell lines via a ROS-dependent mechanism. The aim of the present study was to evaluate whether this combined effect of As 2 O 3 and DHA is also applicable to Several studies have shown that exogenous polyunsaturated fatty acids (PUFAs) may sensitize tumor cells to reactive oxygen species (ROS)-inducing anticancer drugs both in vitro and in vivo. [1][2][3][4][5][6][7] It has been shown that the susceptibility of PUFAs to lipid peroxidation is of pivotal importance for this drug-enhancing effect. 2,4,7 The ROS-generating anticancer drug arsenic trioxide (As 2 O 3 ) has been used for the treatment of several types of leukemia with remarkable clinical success. 8 -12 Although several mechanisms of action have been proposed for the antileukemic activity of As 2 O 3 , the generation and accumulation of ROS most likely constitutes the key mechanism responsible for its cytotoxic action. 13,14 However, clinically achievable concentrations (1-2 M) of As 2 O 3 are not effective in all tumor types. 15 Hence, investigations to enhance the effect of As 2 O 3 without increasing its concentration have been impelled. 16,17 Recently, we showed that the PUFA docosahexaenoic acid (DHA) enhances the apoptotic effect of clinically achievable concentrations (1 M) of As 2 O 3 in As 2 O 3 -resistant leukemia cells. 18 The combined effect of As 2 O 3 and DHA was due to the induction of apoptosis and associated with accumulation of intracellular ROS and increased production of toxic lipid peroxidation products. Importantly, the combined effect of As 2 O 3 and DHA was not restricted to one type of leukemia cells, but was effective in cells derived from several hematologic malignancies. As a consequence, we hypothesized that the combined effect of As 2 O 3 /DHA treatment may also be applicable to solid tumor cells that are known to be intrinsically less sensitive to As 2 O 3 . To elucidate whether a possible enhancing effect of DHA was PUFA-specific and to define the relationship between enhanced lipid peroxidation and increased As 2 O 3 toxicity, we also tested the effects of oleic acid (OA), a nonperoxidizable monounsaturated fatty acid, on As 2 O 3 -mediated apoptosis. Finally, we also determined the efficacy of As 2 O 3 and DHA in the presence of the lipophilic antioxidant vitamin E. MATERIAL AND METHODS ChemicalsNinety-nine percent pure cis-4,7,10,13,16,19-DHA and cis-9-OA, dl-␣-tocopherol (vitamin E) and As 2 O 3 (Sigma Chemical, St. Louis, MO) were prepared as stock solutions and dissolved to the respective working concentrations with complete culture medium before use as described previously. 18

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

“…6 In addition, other studies have shown that DHA incorporation causes excessive lipid peroxidation and makes tumor cells prone to destruction. For example, the synergistic effects of DHA and arsenic acid in Daudi, SH-1, SK-Br-3, HT-29, SW-620, and PC-3 cell lines 3 and the synergistic effects of DHA and paclitaxel in BT-474 and SK-BR-3 cell lines 25 have been linked to lipid peroxidation. Furthermore, DHA has also been shown to directly modulate the activities of intracellular mediators involved in cell survival and apoptosis including NFkB, PPARa, MAP kinase, AKT, COX-2, Bcl2, and Bax.…”

Arsenic trioxide synergizes with B7H3‐mediated immunotherapy to eradicate hepatocellular carcinomas

“…As 2 O 3 was found to induce the apoptosis of various cancer cell lines, including human hepatocarcinoma cell lines, 13 and inhibited their growth in vitro, but the concentrations of As 2 O 3 required were higher than those used against hematologic malignancies and not clinically achievable without the risk of As 2 O 3 -mediated side effects. Consequently, a search for agents suited to increase the efficacy of As 2 O 3 against less sensitive solid tumors was initiated, [30][31][32] based on the results achieved with APL. 33 Strategies to reduce its toxicity, including local delivery, were also devised.…”

Docosahexaenoic fatty acid (DHA) in the regulation of colon cell growth and cell death: A review

“…DHA also enhanced the apoptotic effect of arsenic trioxide (As 2 O 3 ) in resistant solid tumour cell lines including colon by increasing intracellular ROS and lipid peroxidation products. The effect seems to be tumour-specific because no reduction in cell viability was observed in normal skin fibroblasts 124 . Some studies have shown that altering tumour fatty acid composition by DHA enrichment changes the drugresistant phenotype to a drug-sensitive one 13 .…”