Docosahexaenoic Acid Induces Oxidative DNA Damage and Apoptosis, and Enhances the Chemosensitivity of Cancer Cells

Abstract

The human diet contains low amounts of ω-3 polyunsaturated fatty acids (PUFAs) and high amounts of ω-6 PUFAs, which has been reported to contribute to the incidence of cancer. Epidemiological studies have shown that a high consumption of fish oil or ω-3 PUFAs reduced the risk of colon, pancreatic, and endometrial cancers. The ω-3 PUFA, docosahexaenoic acid (DHA), shows anticancer activity by inducing apoptosis of some human cancer cells without toxicity against normal cells. DHA induces oxidative stress and oxidative DNA adduct formation by depleting intracellular glutathione (GSH) and decreasing the mitochondrial function of cancer cells. Oxidative DNA damage and DNA strand breaks activate DNA damage responses to repair the damaged DNA. However, excessive DNA damage beyond the capacity of the DNA repair processes may initiate apoptotic signaling pathways and cell cycle arrest in cancer cells. DHA shows a variable inhibitory effect on cancer cell growth depending on the cells’ molecular properties and degree of malignancy. It has been shown to affect DNA repair processes including DNA-dependent protein kinases and mismatch repair in cancer cells. Moreover, DHA enhanced the efficacy of anticancer drugs by increasing drug uptake and suppressing survival pathways in cancer cells. In this review, DHA-induced oxidative DNA damage, apoptotic signaling, and enhancement of chemosensitivity in cancer cells will be discussed based on recent studies.

Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review

“…We recently summarized that oxidized DHA leads to DNA adduct formation. Oxidative DNA damage triggers cell cycle arrest and apoptosis by p53-dependent and p53-independent pathways in cancer cells 30. Zhang et al31 reported that DHA and EPA inhibits proliferation and induce apoptosis of human SW 1990 pancreatic cancer cells by down-regulating cyclin E expression.…”

Protective Effects of ω-3 PUFA in Anthracycline-Induced Cardiotoxicity: A Critical Review

“…Several preclinical (in vitro and in vivo) studies and some human experimental studies have demonstrated the ability of ω-3 PUFA to decrease cancer cell proliferation, to promote cancer cell death and to inhibit neoangiogenesis in cancer [ 47 , 48 , 49 ]. Interestingly, these anticancer effects are induced by ω-3 PUFA only in cancer cells and not in normal cells [ 50 ].…”

“…Overall, the suppression of cell survival pathways and induction of cell death are among the most important mechanisms to explain the chemosensitizing effects of these fatty acids in a variety of cancers [ 13 ]. The suppression of cancer cell stemness has also been recently reported [ 68 ], and multiple results have suggested that oxidative stress-induced cytotoxicity plays a central role [ 13 , 48 , 68 ], particularly if the drugs used in combination with ω-3 PUFA were themselves inducers of oxidative stress (such as ATC, or disulfiram) [ 68 ].…”

Biphasic ROS production, p53 and BIK dictate the mode of cell death in response to DNA damage in colon cancer cells

“…Additionally, NAC pretreatment reduced FOXO3-induced early ROS peak, which was shown to be essential for the secondary apoptosis-inducing ROS peak[ 47 ]. Furthermore, docosahexaenoic Acid (DHA) was shown to trigger ROS, p53 activation and cell death in multiple cancer cell lines including colon cancer cells, which could be prevented by pretreatment with antioxidants including NAC[ 48 ]. To explore the involvement of ROS production in DNA damage-induced cell death in HCT-116 wt and p53 -/- cells, we pretreated the cells with NAC or TIRON followed by treatment with cisplatin or UV and we measured the cell viability by CellTiterGlo cell viability assay.…”