Hong S P, Ha S H, Park I S, Kim W H
Department of Internal Medicine, Pundang Cha Hospital, Pochon Cha Medical University, Sungnam, Seoul, Korea.
Yonsei Med J. 1998 Aug;39(4):287-95. doi: 10.3349/ymj.1998.39.4.287.
Epidemiological studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of colon cancer. In addition, NSAIDs reduce the number and size of polyps in patients with familial adenomatous polyposis. The mechanisms of the anti-neoplastic effect of NSAIDs are still far from complete understanding, but one possible mechanism is the induction of apoptosis. Several lines of evidence suggest that NSAIDs-induced apoptosis in colon cancer cells are mediated through the cyclooxygenase (COX)-independent pathway. In this study we explored the mechanism of NSAIDs-induced apoptosis in the colon cancer cell line, HT-29. We confirmed that NSAIDs induce apoptosis in HT-29 cells irrespective of their COX-selectivity. Indomethacin enhanced the expression of p21waf-1 in HT-29 cells. However the expression of apoptosis-related genes such as Fas, bcl-2 and bax was not affected by indomethacin. Intra- and extra-cellular calcium chelators, protein tyrosine kinase (PTK) inhibitor, protein kinase A (PKA) inhibitor and protein kinase C (PKC) inhibitors did not influence indomethacin-induced apoptosis in HT-29 cells. We concluded that NSAIDs-induced apoptosis in colon cancer cells may be independent from signals transducted through [Ca++]i, PTK, PKA, PKC or the expression of apoptosis-related genes. In contrast, our results demonstrating the induction of p21waf-1 transcription by NSAIDs suggest the possible association of NSAIDs-induced apoptosis and cell-cycle control in colon cancer cells.
流行病学研究表明，非甾体抗炎药（NSAIDs）可降低结肠癌的发病率。此外，NSAIDs可减少家族性腺瘤性息肉病患者息肉的数量和大小。NSAIDs抗肿瘤作用的机制仍远未完全明确，但一种可能的机制是诱导细胞凋亡。多项证据表明，NSAIDs诱导结肠癌细胞凋亡是通过不依赖环氧化酶（COX）的途径介导的。在本研究中，我们探讨了NSAIDs诱导结肠癌细胞系HT-29凋亡的机制。我们证实，无论NSAIDs的COX选择性如何，它们均可诱导HT-29细胞凋亡。吲哚美辛可增强HT-29细胞中p21waf-1的表达。然而，Fas、bcl-2和bax等凋亡相关基因的表达不受吲哚美辛的影响。细胞内和细胞外钙螯合剂、蛋白酪氨酸激酶（PTK）抑制剂、蛋白激酶A（PKA）抑制剂和蛋白激酶C（PKC）抑制剂均不影响吲哚美辛诱导HT-29细胞凋亡。我们得出结论，NSAIDs诱导结肠癌细胞凋亡可能独立于通过细胞内钙离子浓度（[Ca++]i）、PTK、PKA、PKC或凋亡相关基因表达所传导的信号。相反，我们的结果表明NSAIDs可诱导p21waf-1转录，这提示NSAIDs诱导的凋亡与结肠癌细胞的细胞周期调控可能存在关联。
