DV128促進DNA損傷藥物之乳癌細胞毒殺作用

DV128 enhances the cytotoxic effects of DNA- damaging agents against human breast cancer cells

郭姵伶(Pei-Ling Kuo)

指導教授 ： 吳志中

高雄醫學大學/藥學院/天然藥物研究所碩士班/碩士(2013年)

摘要

乳癌在世界上女性的癌症及致死率當中比例相當高。儘管DNA損傷劑有嚴重的副作用，DNA損傷療法仍為使用非手術中最常用的有效抗癌治療策略。雖然此種策略可殺死癌細胞，但同時也可能造成特殊傷害及使正常組織產生突變。藥物聯合治療是一個關鍵的策略，以提高治療的療效和減少DNA損傷劑不良影響。化合物DV128是一種黃酮類 protoapigenone人工的合成衍生物，protoapigenone 已被證明作為一種有效的抗癌劑。在這項研究中，我們評估了DV128的細胞毒作用，以及併用DNA損傷劑（mitomycin C和cisplatin）對兩種人類乳腺癌細胞株（MDA-MB-231和MCF-7）的效果。在MTT試驗當中發現，DV128可有效的加強mitomycin C和cisplatin抑制乳癌細胞的增生和群落生成，且可誘導細胞凋亡。DV128 和DNA損傷藥物作用可減少Bcl-2家族的蛋白質表現，且可活化caspase-3, -8, 和 -9。合併使用DV128 和DNA損傷藥物可使JNK和P38活化。此外，抗氧化劑N-acetyl-L-cysteine可防止合併使用cisplatin時造成的細胞死亡。總結上述結果，DV128可增強DNA損傷藥之細胞毒殺及細胞凋亡，且ROS及JNK/ P38的活化可能也和增進合併的效能有關。
關鍵字: DNA損傷劑;藥物聯合治療; DV128; protoapigenone。

關鍵字

DNA損傷劑 ； 藥物聯合治療 ； DV128 ； protoapigenone。

並列摘要

Breast cancer is the cancer with the highest prevalence among women, and the major cause of death worldwide. Drug combination therapy is a key strategy to improve treatment efficacy and to reduce adverse effects of DNA-damaging agents. Compound DV128 is a synthetic derivative of the flavonoid protoapigenone, which has been shown as a potent anticancer agent. In this study, we evaluated the cytotoxic effect of DV128 alone or in combination of DNA-damaging agents (mitomycin C and cisplatin) against two human breast cancer cell lines (MDA-MB-231 and MCF-7). In MTT assay, DV128 alone had only little effect on the viability of breast cancer cells. However, DV128 significantly enhanced the effects of mitomycin C and cisplatin on inhibiting proliferation, clonogenic survival, and inducing apoptosis in breast cancer cells. DV128 in combination of DNA-damaging agents reduced Bcl-2 expression and activated caspase-3, -8, and -9. Phosphorylation of JNK and P38 was stimulated by treatment with DV 128 plus DNA-damaging agents. In addition, the antioxidant N-acetyl-L-cysteine prevented the combination-induced cell death. In conclusion, we have demonstrated that DV128 potentiates DNA-damaging agent-induced cytotoxicity and apoptosis in human breast cancer cells. ROS and JNK/ P38 activation by DV128 may play a crucial role in the combination effect.

Key words: DNA-damaging agent; drug combination therapy; DV128; protoapigenone.

並列關鍵字

DNA-damaging agent ； drug combination therapy ； DV128 ； protoapigenone.

參考文獻

參考文獻

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