Neuropeptide Y improves cisplatin-induced bone marrow dysfunction without blocking chemotherapeutic efficacy in a cancer mouse model

摘要

Cisplatin is the most effective and widely used chemo-therapeutic agent for many types of cancer. Unfortunately, its clinical use is limited by its adverse effects, notably bone marrow suppression leading to abnormal hematopoiesis. We previously revealed that neuropeptide Y (NPY) is responsible for the maintenance of hematopoietic stem cell (HSC) function by protecting the sympathetic nervous system (SNS) fibers survival from chemotherapy-induced bone marrow impairment. Here, we show the NPY-mediated protective effect against bone marrow dysfunction due to cisplatin in an ovarian cancer mouse model. During chemotherapy, NPY mitigates reduction in HSC abundance and destruction of SNS fibers in the bone marrow without blocking the anticancer efficacy of cisplatin, and it results in the restoration of blood cells and amelioration of sensory neuropathy. Therefore, these results suggest that NPY can be used as a potentially effective agent to improve bone marrow dysfunction during cisplatin-based cancer therapy. The majority of cancer therapies are based on chemotherapeutic agents with cytotoxic effects, which cause cancer cell death by directly damaging DNA or by inhibiting cell division. Unfortunately, these agents are non-specific, thus, their administration often induces extended toxic effects in normal tissue as well (1). Cisplatin, which is one of the most widely used chemotherapeutic drugs (2–5), has been employed for the treatment of solid cancers such as ovarian, testicular, uterine, breast, stomach, brain, head-neck, and lung cancer (6–9). Although cisplatin has potent anticancer effects, its use is limited by various side effects such as neurotoxicity, nephrotoxicity, ototoxicity, and particularly bone marrow suppression (4, 10–13). Cisplatin-induced bone marrow damage is accompanied by acute nerve injury in the bone marrow (BM), resulting in sensory and autonomic neuropathy. Patients that have previously received cisplatin show irreversible chronic bone marrow failure, leading to the impairment of hematopoietic stem cells (HSCs) and bone marrow regeneration (13–15). Therefore, it is important to prevent bone marrow dysfunction during conventional chemotherapy using cisplatin without diminishing its anticancer efficacy. Neuropeptide Y (NPY) is secreted from the brain or sympathetic nerves in the autonomic system and its involvement in a variety of physiological processes, including food intake, energy storage, anxiety, stress, and pain perception, is well known (16–18). Several studies have reported that NPY is implicated in the regulation of cell death processes (19). Particularly, our recent study demonstrated that NPY can prevent sensory neuropathy and reduction in HSC abundance by protecting sympathetic nervous system (SNS) fibers in cisplatin-treated mice, suggesting the therapeutic potential of NPY to improve chemotherapy-induced bone marrow suppression (20, 21). In this study, we have indeed demonstrated the protective effect of NPY against cisplatin-induced bone marrow dysfunction in a mouse model of ovarian cancer. Moreover, we found that NPY did not influence the chemotherapeutic effects of cisplatin, while protecting against reduction in HSC abundance and nerve injury from bone marrow impairment, suggesting its potential clinical utility as a protective agent for patients treated with chemotherapy. NPY does not affect the anticancer efficacy of cisplatin in an ovarian cancer mouse model Prior to determining the mitigating effect of NPY on cisplatin-induced bone marrow damage in a mouse model of cancer, we first tested whether NPY has influence on the anticancer efficacy of cisplatin. To establish a cancer xenograft mouse model, A2780 human ovarian cancer cells were transplanted subcutaneously in female athymic nude mice. After cancer establishment, the mice were randomized into 3 groups. One group was subjected to intraperitoneal injection (i.p.) with 10 mg/kg cisplatin, the second group was treated with 10 mg