WL-276, an antagonist against Bcl-2 proteins, overcomes drug resistance and suppresses prostate tumor growth.
WL-276, an antagonist against Bcl-2 proteins, overcomes drug resistance and suppresses prostate tumor growth.
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DOI：
10.1158/0008-5472.can-07-6590
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发表时间：
2008-06
期刊：
影响因子：
11.2
通讯作者：
Liangyou Wang;Daniel T. Sloper;Sadiya N. Addo;Defeng Tian;J. Slaton;Chengguo Xing
中科院分区：
文献类型：
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作者：
Liangyou Wang;Daniel T. Sloper;Sadiya N. Addo;Defeng Tian;J. Slaton;Chengguo Xing
由于获得性耐药，难治性前列腺癌（HRPC）患者的估计中位生存期仅为10个月，因此迫切需要开发针对耐药HRPC表型的治疗方法。越来越多的证据表明，过表达抗凋亡Bcl-2家族蛋白至少部分负责HRPC患者的耐药性的发展。因此，拮抗抗凋亡Bcl-2家族蛋白是一种潜在的方法，以规避耐药性HRPC。WL-276被开发为抗凋亡Bcl-2家族蛋白的小分子拮抗剂，其结合效力与（-）-棉酚相当。过表达Bcl-2或Bcl-X（L）不能赋予对WL-276的抗性。WL-276还有效地诱导PC-3细胞凋亡。此外，对标准癌症化疗具有获得性耐药性的三种PC-3细胞系对WL-276比亲本PC-3细胞系更敏感。对耐药PC-3细胞的细胞毒性增加表明WL-276对常规疗法耐药的HRPC的临床潜力。WL-276的抗癌活性表现在其在体内抑制PC-3诱导的前列腺肿瘤生长。WL-276对耐药PC-3细胞的选择性毒性及其对PC-3前列腺肿瘤生长的体内抑制表明，WL-276是开发针对耐药HRPC的Bcl-2拮抗剂的有希望的主要候选物。
Patients with hormone-refractory prostate cancer (HRPC) have an estimated median survival of only 10 months because of acquired drug resistance, urging the need to develop therapies against the drug-resistant HRPC phenotype. Accumulating evidence suggests that overexpressing antiapoptotic Bcl-2 family proteins is at least partially responsible for the development of drug resistance among HRPC patients. Antagonizing the antiapoptotic Bcl-2 family proteins, therefore, is one potential approach to circumventing drug resistance in HRPC. WL-276 was developed as a small-molecule antagonist against antiapoptotic Bcl-2 family proteins, with binding potency comparable to (-)-gossypol. Overexpressing Bcl-2 or Bcl-X(L) failed to confer resistance to WL-276. WL-276 also effectively induced apoptosis in PC-3 cells. In addition, three PC-3 cell lines with acquired drug resistance against standard cancer chemotherapies were more sensitive to WL-276 than the parent PC-3 cell line. The increased cytotoxicity toward drug-resistant PC-3 cells shows the clinical potential of WL-276 against HRPC that is resistant to conventional therapies. The anticancer activity of WL-276 was manifested in its suppression of PC-3-induced prostate tumor growth in vivo. The selective toxicity of WL-276 against drug-resistant PC-3 cells and its in vivo suppression of PC-3 prostate tumor growth suggest that WL-276 is a promising lead candidate for the development of Bcl-2 antagonists against drug-resistant HRPC.