Tauchi Tetsuzo, Shin-Ya Kazuo, Sashida Goro, Sumi Masahiko, Nakajima Akihiro, Shimamoto Takashi, Ohyashiki Junko H, Ohyashiki Kazuma
First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
Oncogene. 2003 Aug 14;22(34):5338-47. doi: 10.1038/sj.onc.1206833.
The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.
端粒酶复合物负责端粒的维持，是一个很有前景的肿瘤治疗靶点。为了确定G-四链体相互作用的端粒酶抑制剂端粒抑素（SOT-095）是否可能对端粒动态变化有影响并评估其临床效用，我们评估了端粒抑素对BCR-ABL阳性人类白血病细胞的作用。我们发现，用端粒抑素处理可重复性地抑制BCR-ABL阳性白血病细胞系OM9;22和K562中的端粒酶活性，导致端粒缩短。端粒抑素对端粒酶活性的抑制会破坏端粒的维持，最终导致端粒功能障碍。端粒抑素在1 microM时完全抑制了K562细胞的接种效率；然而，端粒抑素对正常骨髓CD34阳性细胞的BFU-Es和CFU-GMs集落形成的影响较小。在端粒抑素处理的K562细胞中还观察到对伊马替尼和化疗药物的化疗敏感性增强。此外，端粒抑素加伊马替尼的联合用药更有效地抑制了原发性人类慢性粒细胞白血病细胞的造血集落形成。最后，端粒抑素诱导了ATM和Chk2的激活，随后增加了p21(CIP1)和p27(KIP1)的表达。这些结果表明，端粒抑素诱导的端粒功能障碍激活了ATM依赖性DNA损伤反应。我们得出结论，端粒酶抑制剂与伊马替尼和其他化疗药物联合使用可能对人类白血病的治疗非常有用。
