## 4 Interactions of n-3 PUFA with Other Antineoplastic Drugs  
The management of melanoma poses considerable challenges owing to the intricate nature of the disease, characterized by the emergence of diverse cancer cell subtypes that demonstrate resistance to conventional chemotherapeutic interventions, exemplified by cisplatin administration. Over time, melanoma cells acquire resistance mechanisms against cisplatin, exacerbating therapeutic complexities. Nevertheless, the incorporation of n-3 PUFAs presents a promising adjuvant therapeutic strategy, potentially reinstating the sensitivity of melanoma cells to cisplatin. Notably, findings from an in vitro investigation revealed a synergistic interaction between DHA and cisplatin, accentuating growth inhibition within melanoma cell lines. In the context of wound healing assays, the combined application of these constituents exhibited a synergistic effect, notably attenuating the invasive potential of melanoma cells. Cisplatin-induced reduction in dual specificity phosphatase 6 (DUSP6) levels elicits heightened p-ERK 12, thereby augmenting the DNA-repair machinery within melanoma cells, thus elucidating the incremental resistance observed in melanoma progression. In contrast, DHA intervenes in this DNA-repair pathway by upregulating DUSP6 phosphatase expression, thereby engendering the synergistic therapeutic outcome delineated previously [128]. Similar outcomes are observed upon the administration of EPA concurrent with 5-fluorouracil (5-FU) treatment, whereby connexin 43 (Cx43) modulation is implicated. Notably, cell viability decreases in EPA-treated cells compared to untreated counterparts, and these cells exhibit enhanced sensitivity to chemotherapy [129]. Furthermore, emerging evidence suggests that n-3 PUFAs may serve as a plausible adjunctive therapeutic modality to potentiate the efficacy of doxorubicin. 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]. Elevated expression levels of these proteins in drug-resistant cancer phenotypes precipitate heightened drug efflux and concomitant attenuation of drug accumulation, hence highlighting their pivotal roles in chemotherapeutic resistance mechanisms [134; 135]. However, to understand completely the mechanisms, further studies are needed. In addition, an n-3 PUFA supplementation has been shown to be effective in reducing kidney and liver doxorubicin-induced damage in mice [136], and has even been observed to be effective in reducing the early doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia [137]. These effects are suspected to be related to the inhibition of NADPH oxidase 4, oxidative stress and apoptosis [138]. Subsequent investigations by other researchers have unveiled a synergistic relationship between DHA and docetaxel. Specifically, isoforms of protein kinase C (PKC), PKC\(\varepsilon\) and PKC\(\delta\), have garnered attention in this context. PKC\(\varepsilon\) is known to promote cell proliferation and differentiation, while PKC\(\delta\) is implicated in apoptotic processes. Notably, both isoforms have been implicated in conferring chemoresistance to docetaxel through activation of the ERK pathway precipitated by the therapeutic intervention [139; 140]. A study has reported that administration of docetaxel resulted in elevated expression levels of PKC\(\varepsilon\) and PKC\(\delta\) within both membrane and nuclear subcellular fractions.