Lung cancer is the most common cause of cancer associated mortality. Chemotherapeutic agents, such as paclitaxel, are important treatment options but drug resistance often develops upon prolonged use. We report here the preclinical evaluation of a new orally available tubulin inhibitor, VERU-111, which can overcome several ABC-transporters mediated multi-drug resistance associated with taxane treatment. In vitro, VERU-111 prevents cell proliferation, invasion, migration and colony formation in both paclitaxel-sensitive and paclitaxel-resistant A549 lung cancer cells. VERU-111 effectively inhibits tubulin polymerization, arrests cells in G2/M phase, and induces cancer cell apoptosis. Further evaluation of various apoptotic proteins revealed that treatment of VERU-111 increases the expression of cleaved-PARP, cleaved-caspase-3 and p-histone H3 proteins. In vivo, orally administered VERU-111 in a paclitaxel-sensitive A549 xenograft model strongly inhibits tumor growth in a dose-dependent manner and is equally potent with paclitaxel. When tested in a highly paclitaxel-resistant A549/TxR tumor model, VERU-111 is as effective as the parental A549 model in significantly reducing the tumor volume, whereas paclitaxel is essentially ineffective. Collectively, this study showed that VERU-111 is a promising new generation of anti-tubulin agent for the treatment of taxane-resistant lung cancer.

肺癌是癌症相关死亡的最常见原因。化疗药物，如紫杉醇，是重要的治疗选择，但长期使用往往会产生耐药性。我们在此报告了一种新型口服微管蛋白抑制剂 VERU-111 的临床前评估，该抑制剂可以克服与紫杉烷治疗相关的几种 ABC 转运蛋白介导的多药耐药性。在体外，VERU-111 可防止紫杉醇敏感和紫杉醇抗性 A549 肺癌细胞中的细胞增殖、侵袭、迁移和集落形成。VERU-111 有效抑制微管蛋白聚合，使细胞停滞在 G2/M 期，并诱导癌细胞凋亡。对各种凋亡蛋白的进一步评估表明，VERU-111 的处理增加了裂解 PARP 的表达，cleaved-caspase-3 和 p-histone H3 蛋白。在体内，在紫杉醇敏感的 A549 异种移植模型中口服 VERU-111 以剂量依赖性方式强烈抑制肿瘤生长，并且与紫杉醇同样有效。在高度抗紫杉醇的 A549/TxR 肿瘤模型中进行测试时，VERU-111 在显着减少肿瘤体积方面与亲代 A549 模型一样有效，而紫杉醇基本上无效。总的来说，这项研究表明 VERU-111 是一种很有前途的新一代抗微管蛋白药物，用于治疗紫杉烷耐药性肺癌。VERU-111 在显着减少肿瘤体积方面与亲代 A549 模型一样有效，而紫杉醇基本上无效。总的来说，这项研究表明 VERU-111 是一种很有前途的新一代抗微管蛋白药物，用于治疗紫杉烷耐药性肺癌。VERU-111 在显着减少肿瘤体积方面与亲代 A549 模型一样有效，而紫杉醇基本上无效。总的来说，这项研究表明 VERU-111 是一种很有前途的新一代抗微管蛋白药物，用于治疗紫杉烷耐药性肺癌。