Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival for non-small-cell lung cancers
Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival for non-small-cell lung cancers
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DOI：
10.1016/j.lungcan.2007.08.026
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发表时间：
2008-02-01
期刊：
影响因子：
5.3
通讯作者：
Yeh, Kun-Yun
中科院分区：
文献类型：
--
作者：
Li, Ying-Ying;Chang, John W. -C.;Yeh, Kun-Yun
背景资料：唑来膦酸（zoledronic acid，ZOL）是第三代含氮双膦酸盐，目前已被广泛用于乳腺癌、前列腺癌、多发性骨髓瘤和小细胞肺癌的治疗，但其对非小细胞肺癌（non-small-cell lung cancer，NSCLC）的治疗作用仍有待进一步研究。本研究使用与人肺腺癌行为相似的小鼠肺腺癌细胞系，检测ZOL对1系肿瘤细胞的作用。我们研究了ZOL的抗肿瘤作用（3 - 100 μ M）在体外对1号线肿瘤细胞的作用，包括细胞增殖，通过MTT测定，通过流式细胞术进行细胞周期分析，并通过膜联蛋白V/碘化丙啶（PI）和4 ′-6-二脒基-2-苯基吲哚（DAPI）染色评估凋亡水平。此外，我们使用动物模型评估了ZOL治疗（1 μ g/kg/周）后1系肿瘤细胞的生长和存活。我们还研究了在体内细胞周期模式使用lacZ表达线-1细胞（线-1/lacZ）。结果：ZOL显着减缓线-1肿瘤生长在体外呈剂量依赖性的方式。经处理的1系肿瘤细胞在ZOL暴露后通常停滞在细胞周期的S/G2/M期，但通过膜联蛋白V/PI或DAPI染色均不能检测到凋亡细胞。当ZOL被冲洗掉时，药物抑制的细胞再次继续增殖，并且药物引起的细胞周期延长提前，然后消失。在药物去除后72 - 96 h内，处理的细胞的细胞周期显示出与未处理的对照相似的分布。体内研究表明，ZOL显着减缓线-1肿瘤生长。事实上，当小鼠接受ZOL治疗时，它们的寿命显著长于未治疗小鼠的情况（p <0.05）。使用线-1/lacZ细胞，在体内细胞周期分布线-1肿瘤细胞后ZOL曝光揭示S/G2/M期阻滞，是相同的体外culture.Conclusions：ZOL保持潜在的降低肿瘤负荷，延长小鼠肺腺癌的生存期。流式细胞术分析细胞周期表明，ZOL不诱导凋亡，但能够将1号线肿瘤细胞阻滞在S/G2/M期。尽管这些结果的临床相关性需要对人类肺癌患者进行验证，但ZOL联合化疗和/或放疗似乎是有效治疗NSCLC的新治疗策略。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
Background: Although zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, has been identified as an attractive therapeutic agent against breast cancer, prostate cancer, multiple myeloma as well as small-cell lung cancer (SCLC), as best as we are aware, the anti-tumor effect of ZOL upon non-small-cell lung cancer (NSCLC) remains to be effectively investigated. This study examined the effects of ZOL upon the line-1 tumor cell, using a murine lung adenocarcinoma cell line similar to the behavior of human lung adenocarcinoma.Methods: We investigated the anti-tumor effects of ZOL (3-100 mu M) on line-1 tumor cells in vitro, including cellular proliferation, by means of an MTT assay, cell-cycle analysis by flow cytometry and by assessing the level of apoptosis by annexin V/propidium iodide (PI) and 4'-6-diamidino-2-phenylindole (DAPI) staining. Further, we evaluated the growth and survival of line-1 tumor cells following ZOL treatment (1 mu g/kg/week) using an animal model. We also examined the in vivo cell-cycle pattern using lacZ-expressing line-1 cells (line-1/lacZ).Results: ZOL significantly slowed the line-1 tumor growth in a dose-dependent manner in vitro. The treated line-1 tumor cells typically arrested at the S/G2/M-phase of the cell-cycle following ZOL exposure, but no apoptotic cells could be detected by either annexin V/PI or DAPI staining. When the ZOL was washed out, the drug-inhibited cells continued to proliferate again and the cell-cycle prolongation elicited earlier by the drug, then disappeared. Within 72-96 h following drug removal, the cell-cycle of the treated cells revealed a similar distribution to that of the untreated controls. In vivo studies demonstrated that ZOL significantly slowed the line-1 tumor growth. Indeed, mice lived significantly longer when they had been ZOL-treated than was the case for untreated mice (p < 0.05). Using line-1/lacZ cells, the in vivo cell-cycle distribution of line-1 tumor cells subsequent to ZOL exposure revealed S/G2/M-phase arrest that was identical to the in vitro culture.Conclusions: ZOL maintains the potential to reduce tumor burden and prolong survival for murine pulmonary adenocarcinoma. The flow cytometrical analysis of cell-cycle demonstrated that ZOL induces no apoptosis but is able to arrest line-1 tumor cells at the S/G2/M-phase. Although the clinical relevance of these results warrants verification for human lung cancer patients, ZOL combined with chemotherapy and/or radiotherapy appears to be a new therapeutic strategy for the effective treatment of NSCLC. (C) 2007 Elsevier Ireland Ltd. All rights reserved.