Time-staggered inhibition of JNK effectively sensitizes chemoresistant ovarian cancer cells to cisplatin and paclitaxel
Time-staggered inhibition of JNK effectively sensitizes chemoresistant ovarian cancer cells to cisplatin and paclitaxel
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DOI：
10.3892/or.2015.4377
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发表时间：
2016-01-01
期刊：
影响因子：
4.2
通讯作者：
Kitanaka, Chifumi
中科院分区：
文献类型：
--
作者：
Seino, Manabu;Okada, Masashi;Kitanaka, Chifumi
卵巢癌是最致命的妇科恶性肿瘤，其中铂和紫杉烷为基础的化疗发挥了重要作用。卵巢癌的化疗耐药性是成功治疗这种毁灭性疾病的主要障碍;然而，克服铂和紫杉烷耐药性的有效措施尚未建立。在本研究中，在研究卵巢癌化疗耐药的机制时，我们发现JNK可能在卵巢癌细胞对顺铂和紫杉醇的耐药性中起关键作用。重要的是，同时应用JNK抑制剂和任何一种化疗药物对顺铂有相反的效果。（增强的细胞毒性）和紫杉醇（细胞毒性降低），在化学治疗剂应用之前的JNK抑制剂处理总是增强两种药物的细胞毒性，这表明，基础JNK活性通常参与卵巢癌细胞对顺铂和紫杉醇的化学抗性，药物诱导的JNK活性，这两种药物可能具有不同的作用。此外，我们使用非转化的人和啮齿类动物成纤维细胞证实，JNK抑制剂和化疗剂的顺序应用不会增加它们的毒性。因此，我们的研究结果首次强调了卵巢癌细胞化疗耐药性中基础和诱导JNK活性的可能差异作用，并表明时间交错的JNK抑制可能是克服卵巢癌对铂和紫杉烷化疗耐药性的合理和有前途的策略。
Ovarian cancer is the most lethal gynecological malignancy, for which platinum- and taxane-based chemotherapy plays a major role. Chemoresistance of ovarian cancer poses a major obstacle to the successful management of this devastating disease; however, effective measures to overcome platinum and taxane resistance are yet to be established. In the present study, while investigating the mechanism underlying the chemoresistance of ovarian cancer, we found that JNK may have a key role in the resistance of ovarian cancer cells to cisplatin and paclitaxel. Importantly, whereas simultaneous application of a JNK inhibitor and either of the chemotherapeutic agents had contrasting effects for cisplatin (enhanced cytotoxicity) and paclitaxel (decreased cytotoxicity), JNK inhibitor treatment prior to chemotherapeutic agent application invariably enhanced the cytotoxicity of both drugs, suggesting that the basal JNK activity is commonly involved in the chemoresistance of ovarian cancer cells to cisplatin and paclitaxel in contrast to drug-induced JNK activity which may have different roles for these two drugs. Furthermore, we confirmed using non-transformed human and rodent fibroblasts that sequential application of the JNK inhibitor and the chemotherapeutic agents did not augment their toxicity. Thus, our findings highlight for the first time the possible differential roles of the basal and induced JNK activities in the chemoresistance of ovarian cancer cells and also suggest that time-staggered JNK inhibition may be a rational and promising strategy to overcome the resistance of ovarian cancer to platinum- and taxane-based chemotherapy.