Investigation of new protective therapy of inner ear using a super anti-apoptotic protein, PTD-FNK

简介：顺铂（Cisplatin，CDDP）是一种铂类抗癌药物，通过DNA损伤诱导细胞凋亡，广泛应用于头颈部恶性肿瘤的治疗。另一方面，CDDP也有一些副作用，如耳毒性、肾毒性和骨髓抑制。耳毒性反应是导致化疗停止的原因之一。由Bcl-x_L构建的超级抗凋亡蛋白FNK具有较强的抑制细胞死亡的活性。HIV/达特蛋白转导结构域（PTD）与FNK的融合蛋白PTD-FNK可进入细胞体内。PTD-FNK可被递送到脑以减轻沙土鼠的缺血性损伤。在此，我们研究了PTD-FNK是否对CDDP诱导的内耳听力损失具有保护作用。在注射CDDP之前2小时注射。将CDDP（17 mg/kg）腹膜内注射到小鼠（C57/BL 6）中。注射后7天，记录ABR并处死动物。结果：CDDP（17 mg/kg）腹腔注射C57/BL 6小鼠，存活率为57%;在第7天，所有存活的小鼠都表现出ABR阈值的升高。CDDP（1.5mg/kg）可抑制荷瘤小鼠肿瘤体积的增加。结论：PTD-FNK不影响CDDP的抑瘤活性。PTD-FNK似乎穿透血-内耳屏障以保护内耳免受CDDP诱导的耳毒性。这些结果表明，PTDFNK在预防抗癌药物副作用引起的正常细胞死亡方面具有很大的临床应用潜力。

Introduction : Cisplatin (CDDP), a platinum-derived anti-cancer drug, induces apoptosis by DNA damage and is widely applied for the patients with head and neck cancer. On the other hand, CDDP has some side effects, such as ototoxicity, nephrotoxicity, and myelosuppression. The ototoxocity is one of the reasons to stop the chemotherapy. The super anti-apoptotic protein FNK, constructed from Bcl-x_L, exhibits the stronger activity to inhibit cell death. The fusion protein PTD-FNK of the HIV/Tat protein transduction domain (PTD) and FNK can enter into the cell body. PTD-FNK can be delivered to the brain to reduce ischemic injury, when i.p.injected into gerbils. Here, we investigated whether PTD-FNK protects inner ear from CDDP-induced hearing loss.Materials and Methods : PTD-FNK was s.c. injected 2 hours before the injection of CDDP. CDDP (17 mg/kg) was i.p.injected into the mice (C57/BL6). 7 days after the injection, ABR was recorded and animals were sacrificed. CDDP (1.5 mg/kg) also injected the tumor carrying mice and measured the tumor growth.Results : When CDDP (17 mg/kg) were i.p. injected into mice (C57/BL6), the survival rate was 57 %. On Day 7, all of the survived mice exhibited the elevation of ABR threshold. CDDP (1.5 mg/kg) inhibited an increase in the volume of tumor, when injected into tumor-carrying mice.Conclusions : PTD-FNK didn't affect the activity of CDDP to inhibit the tumor growth. PTD-FNK seems to penetrate the blood-inner ear barrier to protect inner ear from CDDP-induced ototoxicity. These results suggest that PTDFNK has great potential for clinical applications to prevent death of normal cells caused by side effects of anti-cancer drugs.