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首页> 外文期刊>Journal of cellular biochemistry. >A combined treatment of HeLa cells with the farnesyl protein transferase inhibitor L-744,832 and cisplatin significantly increases the therapeutic effect as compared to cisplatin monotherapy.
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A combined treatment of HeLa cells with the farnesyl protein transferase inhibitor L-744,832 and cisplatin significantly increases the therapeutic effect as compared to cisplatin monotherapy.

机译：与顺铂单药治疗相比，用法呢基蛋白转移酶抑制剂L-744,832和顺铂联合治疗HeLa细胞的疗效显着提高。

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Activating mutations of Ras that frequently occur during malignant transformation, enhance growth-promoting signal transduction, allowing cells to bypass stringent control of cell cycle progression, thereby rendering them highly proliferative. Abundantly expressed c-Ha-ras protein in human cervical HeLa cells is farnesylated and attached to the plasma membrane, inducing enhanced signal transduction. Exposure of HeLa cells to cisplatin very efficiently inhibits cell proliferation and induces apoptosis. Unfortunately, high doses of cisplatin are strongly cytotoxic, therefore, an alternative therapeutic strategy allowing dose reduction of cisplatin by inhibition of farnesylation could increase the curative effects of cisplatin, thereby benefiting cancer patients. We used two inhibitors of farnesyl protein transferase (FPTase), FTI, and L-744,832, to sensitize HeLa cells to the action of cisplatin. The combined administration of cisplatin and inhibitors of FPTase increased the cytostatic potency of cisplatin. L-744,832 exhibited a stronger synergistic effect in combination with cisplatin than FTI. Moreover, the efficiency of the combined therapy strongly depended on the treatment regimen: The highest efficiency was achieved after combined treatment for 24 h and post-incubation with an inhibitor of FPTase for 48 h. Following this optimized treatment, apoptosis was induced in approximately 50% of HeLa cells treated with 1 microM cisplatin, representing approximately a threefold increase as compared to cisplatin monotherapy. Combined treatment of HeLa cells with cisplatin and inhibitors of FPTase significantly increases the efficacy of the therapy and allows to reduce the dose of cisplatin. Importantly, best therapeutic effects can be achieved by post-treatment with inhibitors of FPTase.
机译：在恶性转化过程中经常发生的Ras激活突变，增强了促进生长的信号转导，使细胞可以绕过细胞周期进程的严格控制，从而使其高度增殖。人宫颈HeLa细胞中大量表达的c-Ha-ras蛋白被法尼基化并附着在质膜上，从而诱导增强的信号转导。 HeLa细胞与顺铂接触可非常有效地抑制细胞增殖并诱导凋亡。不幸的是，高剂量的顺铂具有强烈的细胞毒性，因此，允许通过抑制法尼基化来减少顺铂剂量的另一种治疗策略可能会增加顺铂的疗效，从而使癌症患者受益。我们使用了法呢基蛋白转移酶（FPTase），FTI和L-744,832的两种抑制剂来使HeLa细胞对顺铂的作用敏感。顺铂和FPTase抑制剂的联合给药增加了顺铂的细胞抑制能力。 L-744832与顺铂联用比FTI具有更强的协同作用。此外，联合治疗的效率在很大程度上取决于治疗方案：联合治疗24小时和与FPTase抑制剂一起孵育48小时后，可获得最高效率。经过这种优化的治疗后，在约50％的用1 microM顺铂处理的HeLa细胞中诱导了凋亡，这是与顺铂单药疗法相比大约增加了三倍。 HeLa细胞与顺铂和FPTase抑制剂的联合治疗可显着提高治疗效果，并减少顺铂的剂量。重要的是，通过用FPTase抑制剂进行后处理可以达到最佳治疗效果。

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