Cisplatin (cis-diamminedichloroplatinum, CDDP) has been widely used in cancer chemotherapy since its initial discovery [1,2]. This drug is known to inhibit the synthesis of RNA, DNA, and protein in cells [2,3]. However, despite its clinical success, the severe side effects caused by cisplatin limit its application, such as nephrotoxicity, myelosuppression, and neurotoxicity [[4], [5], [6]]. In particular, the severity of myelosuppression can result in treatment delays and even life-threatening consequences. In addition, the reduction of bone marrow (BM) cells is a characteristic of cisplatin-induced myelosuppression [5], indicative of the damage to hematopoietic cells and a hematopoietic microenvironment. Consequently, this will lead to the reduction of peripheral blood erythrocyte, leukocyte, and platelets, and increased risk of infection. Therefore, it is essential to find safe and effective agents that can alleviate the myelosuppression caused by cisplatin.

In chemotherapy and radiation therapy, myelosuppression, also known as bone marrow (BM) suppression or myelotoxicity, is the most common side effect. Suppression of BM production can be due to oxidative stress, anemia, hypoxia, radiation, and cytotoxic chemotherapy [4]. Notably, several studies have revealed that in addition to genetic toxicity, cisplatin can also cause oxidative damage to cells through excessive production of reactive oxygen species (ROS), inhibition of the activity of antioxidant enzymes, and consumption of intracellular glutamate (GSH) [4,7]. The accumulation of ROS will destroy mitochondria, cause a decrease in mitochondrial membrane potential (MMP), damage the respiratory chain, and ultimately trigger apoptosis [7,8]. Previous studies have also reported that diminishing intracellular ROS levels could suppress cisplatin-induced myelosuppression, nephrotoxicity, and neurotoxicity by antioxidant treatment, such as vitamin C, selenium, curcumin, and kinetin [[9], [10], [11]]. However, the precise mechanisms of inhibiting oxidative stress and reducing ROS generation to suppress myelosuppression are still being defined.

ω-3 polyunsaturated fatty acids (PUFAs) such as EPA and DHA compounds are a class of essential fatty acids that must be obtained from the diet. ω-3 PUFAs are well known in anti-inflammatory and antioxidant effects by suppressing lipid peroxidation [12]. The protective effects of ω-3 PUFAs against obesity, dyslipidemia, diabetes, stroke, and liver fibrosis have also been demonstrated in mice [[13], [14], [15], [16], [17]]. Furthermore, supplementation of ω-3 PUFAs improves antioxidant status by the activation of the NRF2 (nuclear factor erythroid 2-related factor) pathway, which can regulate the detoxification of ROS [18]. The antitumor properties of ω-3 PUFAs have also been validated in many published studies, including ours [[19], [20], [21], [22]]. Furthermore, clinical studies indicate that ω-3 PUFAs supplementation could prevent chemoradiotherapy-induced weight loss, inflammation, and neurotoxicity without compromising their antitumor effects [[23], [24], [25]]. Most importantly, ω-3 PUFA supplementation mitigates cancer-related complications, such as pain, depression, anorexia-cachexia, and paraneoplastic syndromes [26]. Thus, ω-3 PUFA supplementation may attenuate oxidative damage and cisplatin-induced myelosuppression.

Accumulating evidence suggests that ω-3 PUFAs can promote hematopoiesis and improvement of a hematopoietic microenvironment [27,28], and alleviate chemotherapy-induced bone marrow damage in animal models [[29], [30], [31]]. They can regulate hematopoietic differentiation by reducing myeloid progenitor cell frequency and enhancing progenitor cell differentiation in the BM [29]. Additionally, DHA supplementation can facilitate megakaryocytes and platelet production by reducing apoptosis and ROS [29], and helps the recovery of hematopoiesis function in sub-lethally irradiated mice [32]. Currently, the protective mechanism of ω-3 PUFAs is unclear in chemotherapy-induced myelosuppression. In this study, we set to explore the effects and underlying mechanisms of ω-3 PUFAs on cisplatin-induced myelosuppression. To this end, we have deployed a previously characterized transgenic mouse model globally overexpressing a C. elegans ω-3 fatty acid desaturase, mfat-1, an enzyme that can elevate tissue content of ω-3 PUFAs by adding a double bond at the ω-3 position in ω-6 PUFAs [15]. In addition to their protective properties, ω-3 PUFAs also compete with ω-6 PUFAs to inhibit their metabolisms. This inhibitory effect has been attributed to competition between ω-3 PUFAs and ω-6 PUFAs for the same metabolic enzymes (LOX and COX) [33]. Therefore, potential confounding factors of diet are eliminated without using dietary supplements.