Free radical derivatives formed from cyclooxygenase-catalyzed dihomo-γ-linolenic acid peroxidation can attenuate colon cancer cell growth and enhance 5-fluorouracil׳s cytotoxicity

Abstract

Dihomo-γ-linolenic acid (DGLA) and its downstream fatty acid arachidonic acid (AA) are both nutritionally important ω–6 polyunsaturated fatty acids (ω–6s). Evidence shows that, via COX-mediated peroxidation, DGLA and its metabolites (1-series prostaglandins) are associated with anti-tumor activity, while AA and its metabolites (2-series prostaglandins) could be tightly implicated in various cancer diseases. However, it still remains a mystery why DGLA and AA possess contrasting bioactivities. Our previous studies showed that DGLA could go through an exclusive C-8 oxygenation pathway during COX-catalyzed lipid peroxidation in addition to a C-15 oxygenation pathway shared by both DGLA and AA, and that the exclusive C-8 oxygenation could lead to the production of distinct DGLA׳s free radical derivatives that may be correlated with DGLA׳s anti-proliferation activity. In the present work, we further investigate the anti-cancer effect of DGLA׳s free radical derivatives and their associated molecular mechanisms. Our study shows that the exclusive DGLA׳s free radical derivatives from C-8 oxygenation lead to cell growth inhibition, cell cycle arrest and apoptosis in the human colon cancer cell line HCA-7 colony 29, probably by up-regulating the cancer suppressor p53 and the cell cycle inhibitor p27. In addition, these exclusive radical derivatives were also able to enhance the efficacy of 5-Fluorouracil (5-FU), a widely used chemo-drug for colon cancer. For the first time, we show how DGLA׳s radical pathway and metabolites are associated with DGLA׳s anti-cancer activities and able to sensitize colon cancer cells to chemo-drugs such as 5-FU. Our findings could be used to guide future development of a combined chemotherapy and dietary care strategy for colon cancer treatment.

Knockdown delta-5-desaturase promotes the formation of a novel free radical byproduct from COX-catalyzed ω-6 peroxidation to induce apoptosis and sensitize pancreatic cancer cells to chemotherapy drugs

“…Previous studies in the colon cancer cell line HCA-7 showed that direct treatment of 8-HOA as well as accumulated endogenous formation of 8-HOA in D5D knockdown and COX-catalyzed DGLA peroxidation can not only inhibit cell growth, but also enhanced the cytotoxicity of the chemotherapy drug 5-FU, likely via a p53-dependent pathway [36,37]. The current study aimed to extend the supposition that D5D knockdown in conjunction with DGLA treatment can also be used to inhibit growth of pancreatic cancer cells via p53 independent pathway, using pancreatic cancer cell line BxPC-3 which has both high COX-2 expression and mutated p53.…”

“…A unique structural moiety in DGLA led to the formation of a novel free radical byproduct, 8-hydroxyoctanoic acid (8-HOA) [35]. More recently, the Qian lab also demonstrated that 8-HOA is the bioactive metabolite responsible for DGLA’s anti-cancer effect [35,36]. Direct treatment with certain level of 8-HOA as well as accumulation of 8-HOA from DGLA-treated cells were also found to be essential to inhibit growth of colon cancer cells (e.g., HCA-7 colony 29, overexpresses COX-2) via arresting the cell cycle in G1 and promoting cell apoptosis in a p53-dependent manner [37].…”

Anti-cancer activities of ω-6 polyunsaturated fatty acids

“…Unfortunately, there have been very limited studies focusing on this topic. Recent research from Qian’s group found that DGLA’s free radical derivatives from lipid peroxidation could inhibit human colon cancer cell growth, [43] while direct treatment with DGLA had no effect on cell proliferation, probably due to effective D5D-catalyzed conversion of DGLA to AA. However, when this conversion was limited by D5D knockdown via siRNA transfection, DGLA treatment led to a significant inhibition in cell growth (unpublished research result from Qian’s group).…”

“…[40–43,81,82] The contribution to the study on lipid peroxidation enables us for the first time to investigate the effect of individual ω-6 free radical metabolites and pathways in cancer development. These studies showed that in addition to a C-15 oxygenation shared by both DGLA and AA, there is a unique C-8 oxygenation pathway present during COX-catalyzed DGLA peroxidation, which can give rise to exclusive DGLA free radicals.…”

“…[40–42] It was recently proposed and demonstrated that the adverse effects from ω-6s may be mainly attributed to AA and its metabolite prostaglandin E2 (PGE2), while DGLA may exert an anti-cancer effect via the production of prostaglandin E1 (PGE1) and the exclusive free radical metabolites from its COX-catalyzed lipid peroxidation. [17–23,38,39,43–45] …”