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探討Carboplatin對腎臟傷害的分子機轉

探討Carboplatin對腎臟傷害的分子機轉.

linus-deleon
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探討Carboplatin對腎臟傷害的分子機轉

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  1. 探討Carboplatin對腎臟傷害的分子機轉 • 多年來癌症佔台灣十大死因的第一位，化學療法是治療癌症很重要的方法。卡鉑 (carboplatin) 是一種在臨床上常見用來治療卵巢癌、乳癌和非小型細胞肺癌的癌症用藥，雖然有很好的治療效果但是卻會對腎臟造成毒性，產生正常細胞損傷或死亡這些副作用。許多文獻指出NFAT (nuclear factor of activated T-lymphocytes) 這種轉錄因子 (transcription factor) 和多種調控細胞凋亡的基因轉錄有關。所以在本篇論文中，我們的研究主題為探討carboplatin對老鼠腎管細胞造成的細胞凋亡現象及其作用的分子機轉。我們的實驗證明了carboplatin會增加NFAT 3從細胞質轉移到細胞核，增加NFAT 3活性，導致下游caspase 層疊 (cascade) 活化造成老鼠腎管細胞凋亡。且carboplatin造成的細胞毒性也和增加NADPH氧化酶 (oxidase) 活性造成自由基的產生有關。除此之外，我們的實驗也證明NFAT 3的活性抑制劑：鈣離子熬合劑 (BAPTA-AM)、鈣調磷酸酶calcineurin抑制劑 (cyclosporin A, CsA) 和活性氧化物清潔劑 (N-acetylcysteine, NAC) 都可以成功的反轉carboplatin造成的細胞凋亡現象。而由於第一型血紅素氧化酶 (heme-oxygenase 1, HO-1) 在多種細胞類型中扮演細胞保護的角色，因此HO-1是否可以保護老鼠腎管細胞對抗carboplatin造成的細胞凋亡現象也是我們研究探討的焦點。實驗結果闡明：HO-1可以藉由增加Bcl-xl蛋白質表現量和降低NADPH氧化酶活性來有效地反轉carboplatin造成的老鼠腎管細胞凋亡現象。因此，HO-1也許可以提供給我們一個新的治療方向以保護老鼠腎管細胞對抗carboplatin造成的毒性。總結以上結果顯示，carboplatin造成的腎臟毒性是經由NFAT 3核轉移現象所造成，且可以被活性氧化物清潔劑 (NAC) 和第一型血紅素氧化酶 (HO-1) 這個抗細胞凋亡和抗氧化分子所終止。

  2. The mechanisms of carboplatin induced renal injury • It is the fact that the mortality from cancer is the top number 1 in Taiwan in many years. Chemotherapy is the most important method to cure cancer. Carboplatin is currently used as a therapeutic drug for ovarian, breast, and non-small cell lung cancers. Although carboplatin is highly effective against some tumors, it has serious side effects including renal toxicity that results in cell damage or cell death. Nuclear factor of activated T-lymphocytes (NFAT), a nuclear transcription factor, regulates the transcription of genes involved in apoptosis. In this research, we examined the effect of carboplatin on renal tubular cell apoptosis and its molecular mechanisms underlying. We demonstrated that carboplatin enhanced NFAT 3 nuclear translocation (from cytosol to nucleus), thereby activating downstream caspase cascade and consequently cell apoptosis. And carboplatin-mediated cell toxicity is associated with free radical generation by the activation of NADPH oxidase. Furthermore, the addition of either NFAT 3 inhibitors, including BAPTA-AM (a calcium chelater), cyclosporin A (a calcineurin inhibitor), or NAC (an antioxidant) had successfully reversed cell apoptosis induced by carboplatin. Because heme-oxygenase 1 (HO-1) played cytoprotection roles in various cell types. So whether HO-1 protects RTC from carboplatin-mediated apoptosis is also a main focus in this investigation. We clearly illustrated that HO-1 was effective to prevent the carboplatin-mediated apoptosis through increased Bcl-xl protein level and decreased NADPH oxidase activity. Therefore, HO-1 might be a novel therapeutic target in prevention of carboplatin toxicity in RTC cells. Taken together, carboplatin-mediated renal toxicity is through the nuclear translocation of NFAT 3, which can be abolished by NAC, a free radical scavenger and HO-1, an antiapoptotic and antioxidative molecule.

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