A Potent Oncolytic Adenovirus Selectively Blocks the STAT3 Signaling Pathway and Potentiates Cisplatin Antitumor Activity in Ovarian Cancer
A Potent Oncolytic Adenovirus Selectively Blocks the STAT3 Signaling Pathway and Potentiates Cisplatin Antitumor Activity in Ovarian Cancer
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一种有效的溶瘤腺病毒选择性阻断 STAT3 信号通路并增强顺铂在卵巢癌中的抗肿瘤活性。
DOI：
10.1089/hum.2011.101
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Ma, Ding
中科院分区：
文献类型：
--
作者：
Han, Zhiqiang;Hong, Zhenya;Ma, Ding
以顺铂为中心的化疗是治疗卵巢癌的一线药物。然而，耐药性仍然是成功治疗的主要障碍。有证据表明，信号转导和转录激活因子3（STAT3）是化疗耐药的决定因素，它与许多实体瘤的复发有关。不幸的是，由于毒性或有限的生物利用度，目前开发的阻断STAT3信号传导的化合物都没有被认为是一种重要的临床候选物。在这项研究中，我们阐明了STAT3激活在化疗耐药卵巢癌中的意义，并评估了一种新型溶瘤腺病毒（M4）的适用性，该腺病毒旨在特异性耗尽STAT3并逆转卵巢癌中的顺铂耐药性。我们发现，STAT3的异常表达和组成性激活有助于卵巢癌细胞系和卵巢癌组织样本中的顺铂耐药。M4腺病毒可特异性地清除卵巢癌细胞中组成型和诱导型STAT3蛋白以及磷酸化STAT3蛋白。这显著抑制细胞存活并增强顺铂诱导的凋亡。相比之下，正常人脐静脉内皮细胞和人卵巢表面上皮细胞似乎不受M4处理的影响。此外，联合顺铂加M4治疗基本上消除了肿瘤起始细胞富集的群体。在小鼠中，全身腹腔内给予M4可显著增强顺铂的抗肿瘤作用。这些结果表明，M4具有很大的潜力，作为一种治疗对顺铂耐药的人卵巢癌。因此，需要进一步的临床研究。
Cisplatin-centered chemotherapy is the first-line treatment for human ovarian cancer. However, chemoresistance remains a major obstacle to successful treatment. Evidence has indicated that signal transducer and activator of transcription-3 (STAT3) is a determinant of chemoresistance; it was related to tumor recurrence in a large number of solid malignancies. Unfortunately, none of the compounds currently developed to block STAT3 signaling has been considered a serious clinical candidate because of toxicity or limited bioavailability. In this study, we clarified the significance of STAT3 activation in chemoresistant ovarian cancer and assessed the suitability of a novel oncolytic adenovirus (M4) designed to specifically deplete STAT3 and reverse cisplatin resistance in ovarian cancer. We showed that aberrant expression and constitutive activation of STAT3 was instrumental in cisplatin resistance in ovarian cancer cell lines and in ovarian cancer tissue samples. The M4 adenovirus could specifically deplete constitutive and inducible STAT3 and phosphorylated STAT3 proteins in ovarian cancer cells. This significantly inhibited cell survival and enhanced cisplatin-induced apoptosis. In contrast, normal human umbilical vein endothelial cells and human ovarian surface epithelial cells appeared to be unaffected by M4 treatment. Furthermore, a combined cisplatin plus M4 therapy substantially eliminated populations enriched in tumor-initiating cells. In mice, systemic intraperitoneal administration of M4 significantly potentiated the antitumor effect of cisplatin. These results suggest that M4 has great potential as a therapy against cisplatin resistance in human ovarian cancer. Thus, it warrants further clinical investigation.