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

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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.