Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

Abstract

Drug resistance is a well-known and significant obstacle in the battle against cancer, rendering chemotherapy treatments often ineffective. To improve the effectiveness of chemotherapy, researchers are exploring the use of natural molecules that can enhance its ability to kill cancer cells and limit their spread. Docosahexaenoic acid (DHA), a lipid found in marine fish, has been shown to enhance the cytotoxicity of various anti-cancer drugs in vitro and in vivo. While the combined use of chemotherapeutic drugs with DHA demonstrated promising preliminary results in clinical trials, there is still a significant amount of information to be discovered regarding the precise mechanism of action of DHA. As the biological pathways involved in the chemosensitization of already chemoresistant MCF-7 cells are still not entirely unraveled, in this study, we aimed to investigate whether DHA co-treatment could enhance the ability of the chemotherapy drug doxorubicin to inhibit the growth and invasion of MCF-7 breast cancer cells (MCF-7/Dox) that had become resistant to the drug. Upon treating MCF-7/Dox cells with DHA or DHA–doxorubicin, it was observed that the DHA–doxorubicin combination effectively enhanced cancer cell death by impeding in vitro propagation and invasive ability. In addition, it led to an increase in doxorubicin accumulation and triggered apoptosis by arresting the cell cycle at the G2/M phase. Other observed effects included a decrease in the multi-drug resistance (MDR) carrier P-glycoprotein (P-gp) and TG2, a tumor survival factor. Augmented quantities of molecules promoting apoptosis such as Bak1 and caspase-3 and enhanced lipid peroxidation were also detected. Our findings in the cell model suggest that DHA can be further investigated as a natural compound to be used alongside doxorubicin in the treatment of breast cancer that is unresponsive to chemotherapy.

Cellular Basis of Adjuvant Role of n-3 Polyunsaturated Fatty Acids in Cancer Therapy: Molecular Insights and Therapeutic Potential against Human Melanoma

“…An in vitro investigation has demonstrated that DHA exhibits a synergistic interplay with doxorubicin in MCF7 cells, augmenting intracellular drug accumulation [130], thereby corroborating the synergistic therapeutic outcome mentioned earlier. Notably, the downregulation of Pgp and Transglutaminase 2 emerges as a putative mechanism underlying the sensitization of drug-resistant cancer cells to chemotherapy [131][132][133].…”

Marine-Derived Anticancer Agents Targeting Apoptotic Pathways: Exploring the Depths for Novel Cancer Therapies

“…The anti-invasive activity against MDA-MB-231 cancer cells was demonstrated by the upregulation of type II cytoskeletal 1 (KRT1) proteins and keratin [ 261 ]. In addition to these apoptotic processes, ferroptosis was induced, and drug-resistant breast cancer cells’ resistance was reversed by fish-derived 37 [ 262 ]. Compound 37 has been demonstrated to increase the amount of lipid peroxides in the cellular membrane, which could contribute to oxidative stress and apoptosis [ 262 ].…”

“…In addition to these apoptotic processes, ferroptosis was induced, and drug-resistant breast cancer cells’ resistance was reversed by fish-derived 37 [ 262 ]. Compound 37 has been demonstrated to increase the amount of lipid peroxides in the cellular membrane, which could contribute to oxidative stress and apoptosis [ 262 ]. Furthermore, when coupled with Dox as a treatment for drug-resistant carcinomas, marine-derived 37 has demonstrated a synergistic anticancer effect [ 262 ].…”

“…Compound 37 has been demonstrated to increase the amount of lipid peroxides in the cellular membrane, which could contribute to oxidative stress and apoptosis [ 262 ]. Furthermore, when coupled with Dox as a treatment for drug-resistant carcinomas, marine-derived 37 has demonstrated a synergistic anticancer effect [ 262 ]. Clinical trials investigated 37 ’s anticancer potential in addition to chemotherapeutic drugs for patients with breast cancer.…”

Revolutionizing Cardiovascular Health with Nano-Encapsulated Omega-3 Fatty Acids: A Nano-Solution Approach

“…Along with this, ω-3FA ingestion is associated with a lowered prevalence of inflammation [19] through the lowering of pro-inflammatory cytokines triggered by oxidative stress [20,21]. Various studies have also studied the anti-inhibitory effect of ω-3 FAs on cancers [22,23]. Over the decades various preclinical and clinical studies have been conducted using ω-3FAs to show their efficacy in reducing cardiovascular ailments.…”