Lovastain誘導人類口腔癌細胞凋亡機轉之研究

口腔癌為台灣男性十大癌症發生率的第五位。也是台灣地區年增率最高的癌症。儘管近幾年口腔癌在診斷及治技術上有改進，但病人五年存活率並未有顯著改善。因此須尋找新的治療與預防方法來改善整理存活率及生活品質。Lovastatin為膽固醇合成路徑HMG-CoA reductase的抑制劑，臨床上用以降低病人高血脂。近年研究指出，lovastatin可造成大腸癌、乳癌、及頭頸癌細胞凋亡，但其機制並不十分清楚。因此本研究以人類口腔癌細胞株Ca9-22來探討它對口腔癌細胞的影響。結果顯示，以lovastatin處理Ca9-22細胞可明顯抑制其細胞生長，且濃度越高效應更加明顯。西方墨點分析顯示，以4uM的lovastatin處理Ca9-22，subG0/G1細胞數目百分比會明顯的增加，表示 lovastatin可以引起人類口腔癌細胞凋亡。西方墨點法實驗發現，在內生性凋亡路徑中，lovastatin會增加cyochrome c的釋放，以活化下游 caspase-9造成細胞凋亡。但外生性路徑之細胞膜上死亡受體 (TRAILR1、TRAILR2及FAS)皆沒有明顯改變。加入caspase-8和-9抑制劑 (Z-LEHD-FMK, Z-IETD-FMK)時，發現皆可降低lovastatin誘導細胞凋亡現象發生。當lovastatin與Z-LEHD-fmk同時處理細胞時，可減少lovastatin所造成caspase 8活化。但當lovastatin與Z-IETD-fmk同時處理細胞時，無法顯著減少lovastatin造成的caspase 9活化。可見得內生性凋亡路徑在lovastatin所導致之細胞凋亡扮演重要角色。我們同時發現Lovastatin處理後，可使p-ERK、p-p38及p-JNK的表現量上升。N-acetylcysteine 及MAPK pathway抑制劑，可降低lovastatin所導致之細胞凋亡反應。MAPK在lovastatin誘發細胞凋亡中扮演角色有待進一步研究。

關鍵字

口腔癌； lovastatin ；細胞凋亡

並列摘要

Oral cancer is the fifth leading cause of cancer-related deaths in male population in Taiwan. Despite recent advances in radiotherapy and chemotherapy, the survival of patients with oral cancer has not improved significantly. Continues investigation of new chemotherapeutic agents is need. The 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors, also known as statins, are commonly prescribed medications that lower serum cholesterol. Preclinical research performed during the past decade shows that statins have antineoplastic effects in many tumor cell lines. Therefore, we were interested in exploring the potential of lovastatin as an anti-cancer agent in oral cancer cells. We found lovastatin significantly inhibited the cell proliferation of Ca9-22 in a dose-dependent manner. Flow cytometric analysis of DNA content showed that lovastatin treatment induced apoptosis following G1 arrest. Western blotting showed lovastatin increased cytochrome c release and activated caspase-8 and caspase-9. Caspase-9 activation is earlier than caspase-8. The apoptosis could be inhibited by caspase 8 inhibitor (Z-LEHD-FMK) or caspase 9 inhibitor (Z-IETD-FMK). These results demonstrated that the intrinsic apoptotic pathway may play a major role in the lovastatin-induced apoptosis. Pretreatment of cells with N-acetyl cysteine (NAC), MAPKs inhibitors and PI3K/Akt inhibitors inhibited the PARP cleavage. MAPKs, PI3K/Akt pathway and ROS may play important roles in lovastatin-induced apoptosis. Taking together, the chemopreventive potential of lovastatin is required to be further determined with animal model and clinical trails in the future.

並列關鍵字

Lovastatin ； Aapoptosis ； Oral cancer

參考文獻

Notani, K., et al., A case of Sweet's syndrome (acute febrile neutrophilic dermatosis) with palatal ulceration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2000. 89(4): p. 477-9.

14. Singh, B.B., et al., Immunohistochemical evaluation of bcl-2 oncoprotein in oral dysplasia and carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol

1. Notani, K., et al., A case of Sweet's syndrome (acute febrile neutrophilic dermatosis) with palatal ulceration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2000. 89(4): p. 477-9.

2. Ko, Y.C., et al., Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med, 1995. 24(10): p. 450-3.

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國際替代計量

Lovastain誘導人類口腔癌細胞凋亡機轉之研究

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