## 3 Molecular Mechanisms of Omega-3 Fatty Acids in Cancer
### Multidrug-Resistant Cancer  
The efficacy of chemotherapy is significantly contingent upon the susceptibility of cancerous cells within tumors to drugs, a characteristic that may manifest as either inherent or acquired resistance during the course of treatment. Consequently, the emergence of MDR cancer poses a formidable obstacle in cancer therapy, given its propensity to resist a diverse array of drug compounds and therapeutic interventions [113]. Hence, surmounting drug resistance in cancer assumes paramount importance to enhance treatment outcomes. Numerous investigations have demonstrated the chemossitizing properties of n-3 PUFAs, especially DHA. [PERSON] et al. showed that DHA enhanced the cytotoxicity of taxane in a highly metastatic human breast cancer cell line in a dose-dependent manner, a downregulation was also noted of up to 78% of Her-2/neu (known as c-erbB-2) gene and its oncoprotein [114]. DHA was also shown to enhance the cytotoxicity of cisplatin in two human ovarian epithelial cancer cell lines in a dose-dependent manner, along with induction of apoptosis and anti-proliferative effects [115]. A study revealed that DHA increased the tumor sensitivity to docetaxel in human mammary cancer cell lines by downregulating the phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT) and ERK signaling pathways, survival pathways involucrated in cancer cell proliferation [116]. Moreover, [PERSON] et al. showed that DHA dramatically increased arsenic trioxide (As\({}_{2}\)O\({}_{3}\))-mediated apoptosis in As\({}_{2}\)O\({}_{3}\)-resistant cells, which was found to be associated with increased production of intracellular ROS and toxic lipid peroxidation products. This was demonstrated as these results were abolished by vitamin E (VitE) treatment, an antioxidant, or when combining As\({}_{2}\)O\({}_{3}\) with a non-peroxidizable fatty acid such as oleic acid (OA) [117]. Similar results were exhibited by [PERSON] et al., who found that DHA chemossentized human neuroblastoma cell lines to cisplatin, doxorubicin and irinotecan both in chemosensitive and in MDR neuroblastoma cells, and enhanced the cytotoxicity of As\({}_{2}\)O\({}_{3}\) via ROS generation. These results were also significantly decreased when also treated with VitE or OA [118]. Furthermore, [PERSON] et al. reviewed the mechanisms underlying the chemossentizer effects of n-3 PUFAs, highlighting the generation of ROS and lipid peroxidation, as well as increasing drug transport across the cell membrane and intracellular concentration [119]. For instance, a study showed that DHA chemossentized a breast cancer cell line to anthracyclines, such as doxorubicin, in association with post-transcriptional downregulation of glutathione peroxidase, a protector enzyme against hydrogen and lipid peroxidides, suggesting an ROS-enhancing effect of DHA [120]. A prominently identified phenotype in MDR involves the heightened expression of ATP-binding cassette, known as ABC transporters, notably including MDR-related proteins such as P-glycoprotein (Pgp) and breast cancer-resistance protein. These transporters function to confer resistance to cancer cells via the efflux of therapeutic agents, thereby diminishing intracellular drug concentrations [121]. The functionality of many of these transporters has been demonstrated to be substantially reliant on the composition of the cellular membrane as well as its physicochemical properties [122; 123]. Interestingly, it has been observed that n-3 PUFAs may chemosensitive MDR cancer cell lines by integrating into the cellular membrane, thereby potentially altering its composition and fluidity. Moreover, these PUFAs have been implicated in enhancing ROS production and lipid peroxidation, further contributing to the sensitization of MDR cancer cells to chemotherapy [119]. For instance, the activity of Pgp has been linked to its localization within lipid rafts and membrane cholesterol [124; 125]. Lipid rafts represent lipid-driven subcompartments of the cell membrane comprising sphingolipids, cholesterol and specific proteins.