Antitumor Effects of Telomerase Inhibitor TMPyP4 in Osteosarcoma Cell Lines
Antitumor Effects of Telomerase Inhibitor TMPyP4 in Osteosarcoma Cell Lines
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DOI：
10.1002/jor.21451
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发表时间：
2011-11-01
影响因子：
2.8
通讯作者：
Ochi, Mitsuo
中科院分区：
文献类型：
--
作者：
Fujimori, Jun;Matsuo, Toshihiro;Ochi, Mitsuo
端粒在肿瘤中的研究已被广泛报道用于预测预后，并已描述了靶向端粒酶治疗的有效方法，但端粒酶抑制剂在肉瘤细胞中的有效性仍不清楚。在这项研究中，我们研究了端粒酶抑制剂阳离子卟啉TMPyP4对骨肉瘤细胞株端粒酶活性、端粒长度、细胞生长和凋亡的影响。TMPyP4对端粒酶阳性HOS和SAOS-2细胞的端粒酶活性有明显抑制作用，但对MG-63细胞无明显抑制作用。TMPyP4可显著诱导HOS和Saos-2细胞端粒缩短，抑制细胞生长，凋亡率超过17%。在MG-63中，TMPyP4虽然诱导端粒显著缩短，但并未引起端粒酶活性和细胞生长的抑制。治疗后端粒长度HOS为5.60kb，SAOS-2为4.00kb，MG-63为9.89kb。这些结果可能表明，端粒酶活性的丧失和足够的端粒缩短是抑制端粒酶阳性骨肉瘤细胞生长所必需的。TMPyP4不能诱导端粒缩短，但对端粒酶阴性且端粒U2OS极长的细胞生长有明显的抑制作用，凋亡率为22.6%，提示TMPyP4的抗肿瘤作用可能与DNA损伤有关，包括通过G-四链稳定端粒功能障碍，而不依赖于端粒长度。(C)2011年整形外科研究会。由Wiley期刊公司出版，J Orthop Res 29：1707-1711,2011。
Telomere studies in carcinomas have been extensively reported for prognostic utility and effective methods for targeting telomerase therapy has been described, but efficacy of telomerase inhibitor remained unknown in sarcoma cells. In this study, we investigated the effects of telomerase inhibitor cationic porphyrin TMPyP4 on telomerase activity, telomere length, cell growth, and apoptosis in osteosarcoma cell lines. TMPyP4 significantly inhibited telomerase activity in telomerase positive HOS and Saos-2, but not in MG-63. TMPyP4 significantly induced telomere shortening, and inhibition of the cell growth in HOS and Saos-2 with over 17% apoptosis rates. In terms of MG-63, TMPyP4 did not induce inhibition of both telomerase activity and cell growth, although it induced significant telomere shortening. Telomere length after treatment was 5.60 kb in HOS, 4.00 kb in Saos-2, and 9.89 kb in MG-63. These results may suggest that both telomerase activity loss and sufficient telomere shortening are necessary to inhibit cell growth in telomerase positive osteosarcoma cells. TMPyP4 did not induced telomere shortening but significantly inhibited the growth with 22.6% apoptosis rate in telomerase negative with extremely longer telomere-U2OS, may indicating the antitumor effect of TMPyP4 may be related to DNA damage including telomere dysfunction through G-quadruplex stabilization, independent on telomere length. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:1707-1711, 2011.