草酸鉑是第三代的鉑金類化療藥物，經常被使用於治療多種癌症，特別是在結直腸癌的化學治療上。但在臨床上，長期使用草酸鉑治療會引發急、慢性周邊神經病變的副作用，這些症狀主要包含自發性或誘發性的感覺異常、溫度感覺缺失、痛覺過敏以及觸感痛的現象，然而至今仍缺乏有效的藥物可以預防或治療此類由草酸鉑所導致的周邊神經病變。因此，本篇研究的主旨是從各種化合物資料庫中篩選出可有效減緩化療藥物神經毒性的神經保護藥物。透過高通量螢光顯微藥物開發系統進行藥物篩選，並進一步發現化合物CIX4X在體外實驗中對草酸鉑的神經毒性具有最顯著的神經保護效果。接下來我想進一步研究CIX4X潛在的神經保護機制，於是我針對去氧核醣核酸的氧化、鈣離子衡定調節以及粒線體功能這三方面進行測試，首先發現，CIX4X可改善因草酸鉑所引發的去氧核醣核酸氧化損傷以及鈣離子調節失衡的情況，除此之外，CIX4X也可改善神經細胞在草酸鉑治療後粒線體去極化的現象。顧及CIX4X挽救了背根神經節細胞的細胞凋亡，我接著探討是否CIX4X也會影響草酸鉑對癌細胞的細胞毒殺效果，在單獨只給CIX4X的治療組別中發現，CIX4X有些微抑制HT29細胞增生的效果，但在合併草酸鉑治療下，不論在HCT116或HT29大腸癌細胞株都沒有出現協同作用。綜合以上結果，我的研究指出CIX4X可能是限制草酸鉑神經毒性發展的潛在化合物。

Oxaliplatin, a platinum-based chemotherapeutic agent, is used for the treatment of numerous types of cancers, especially colorectal cancer. Clinically, long-term therapy with oxaliplatin leads to side effects of acute and chronic peripheral neuropathy, including paraesthesia, thermo-anesthesia, hyperalgesia, and mechano-allodynia. However, there is no effective medication to prevent or treat oxaliplatin-induced peripheral neuropathy (OIPN). This study aims to identify neuroprotective drugs from various compound libraries, which can ameliorate neurotoxicity provoked by chemotherapeutic agents. By applying an image-based high-content screening system, the compound CIX4X exhibited the most significant neuroprotective effect on oxaliplatin-induced neurotoxicity in vitro. I further investigated the neuroprotective mechanisms of CIX4X via detecting DNA oxidation, Ca2+ homeostasis, and the function of mitochondria. First, CIX4X abolished extensive oxidative DNA damage and reconstituted Ca2+ homeostasis dysregulation provoked by oxaliplatin. Moreover, CIX4X improved mitochondrial depolarization in dorsal root ganglion cells after oxaliplatin treatments. Considering CIX4X rescued oxaliplatin-induced DRG apoptosis, I further studied whether this compound might protect the cancer cells from oxaliplatin-induced cytotoxicity. The application of CIX4X alone showed a minor effect on suppressing HT29 cell proliferation, but no synergistic anticancer effects with oxaliplatin were found on both HCT116 and HT29 colon cancer cell lines. Taken together, these findings indicated that CIX4X might serve as a potential compound to limit the development of oxaliplatin-induced neurotoxicity.

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