Paclitaxel shows cytotoxic activity in human hepatocellular carcinoma cell lines
Paclitaxel shows cytotoxic activity in human hepatocellular carcinoma cell lines
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DOI：
10.1016/s0304-3835(98)00388-7
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发表时间：
1999-02-08
期刊：
影响因子：
9.7
通讯作者：
Gupta, S
中科院分区：
文献类型：
--
作者：
Gagandeep, S;Novikoff, PM;Gupta, S
紫杉醇通过抑制有丝分裂纺锤体形成来稳定微管，并已被发现对几种实体癌有效。为了测试紫杉醇在人 HCC 细胞系中是否具有细胞毒性，我们使用已建立的 HuH-7 和 HepG2 细胞系，测定了细胞数量、DNA 合成率和细胞活力的变化，我们测试了紫杉醇处理的细胞是否发生凋亡， 微管重组和细胞周期限制 研究还检验了维拉帕米的化疗增敏是否增强了紫杉醇的抗肿瘤活性。紫杉醇浓度大于 0.01 μM（LD50，0.8 μM）时，细胞活力受到损害，流式细胞术表明细胞在 G2/M 期积累，免疫染色显示具有特征条带图案的聚合微管。这种 G2/M 限制通过流式细胞术进一步表征，显示紫杉醇处理的细胞中出现细胞周期蛋白 A 和 cdc2 激酶积累。暴露于紫杉醇在 24 小时时减少了[3H]胸苷掺入细胞中的 DNA，但在 72 小时时显着增加，很可能是由于与细胞周期限制相关的 DNA 修复机制。细胞死亡是通过凋亡和非凋亡机制进行的。最后，联合给予化疗增敏剂维拉帕米，剂量低至1μM，使紫杉醇的抗肿瘤功效提高了五倍，并将紫杉醇的LDS改变为0.1μM。研究结果表明，紫杉醇对培养的肝细胞癌细胞具有细胞毒性。紫杉醇治疗肝细胞癌患者的临床研究可能有助于确定其他治疗方法。 (C) 1999 年由爱思唯尔科学有限公司出版。保留所有权利。
Paclitaxel stabilizes microtubules with inhibition of mitotic spindle formation and has been found effective in several solid cancers, To test whether paclitaxel could be cytotoxic in human HCC cell lines, we used established HuH-7 and HepG2 cell lines, Changes in cell number, DNA synthesis rates and cell viability were determined, We tested whether paclitaxel-treated cells underwent apoptosis, microtubular reorganization, and cell cycle restriction Studies also examined whether chemosensitization with verapamil enhanced the antitumor activity of paclitaxel. The cell viability was impaired at greater than 0.01 mu M paclitaxel concentrations (LD50, 0.8 mu M), with flow cytometry indicating accumulation of cells in G2/M, and immunostaining showing polymerized microtubules with characteristic banding patterns. This G2/M restriction was further characterized by flow cytometry, which revealed cyclin A and cdc2 kinase accumulation in paclitaxel-treated cells. Exposure to paclitaxel decreased [3H]thymidine incorporation into DNA in cells at 24 h but this significantly increased at 72 h, most likely due to DNA repair mechanisms related to cell cycle restriction. The cell death was via both apoptotic and non-apoptotic mechanisms. Finally, co-administration of the chemosensitizer verapamil in doses as little as 1 mu M increased the antitumor efficacy of paclitaxel by up to five-fold and changed the LDS, of paclitaxel to 0.1 mu M. The findings indicate that paclitaxel is cytotoxic to cultured hepatocellular carcinoma cells. Clinical studies of paclitaxel in patients with hepatocellular carcinoma may help determine additional therapies. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.