Sakchaisri Krisada, Kim Sun-Ok, Hwang Joonsung, Soung Nak Kyun, Lee Kyung Ho, Choi Tae Woong, Lee Yongjun, Park Chan-Mi, Thimmegowda Naraganahalli R, Lee Phil Young, Shwetha Bettaswamigowda, Srinivasrao Ganipisetti, Pham Thi Thu Huong, Jang Jae-Hyuk, Yum Hye-Won, Surh Young-Joon, Lee Kyung S, Park Hwangseo, Kim Seung Jun, Kwon Yong Tae, Ahn Jong Seog, Kim Bo Yeon
Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
PLoS One. 2017 Mar 15;12(3):e0173311. doi: 10.1371/journal.pone.0173311. eCollection 2017.
We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.
我们已鉴定出小分子STK899704是一种结构新颖的微管蛋白抑制剂。STK899704抑制了多种来源癌细胞系的增殖，其IC50值在0.2至1.0μM之间。STK899704在体外可阻止纯化微管蛋白的聚合，还能使培养细胞中的微管解聚，导致有丝分裂停滞，这与Cdc25C磷酸化增加以及细胞周期蛋白B1和polo样激酶1（Plk1）的积累及细胞凋亡相关。与紫杉醇和阿霉素等许多抗癌药物不同，STK899704对多药耐药癌细胞系有效显示出抗增殖活性。STK899704的拟结合模式是在αβ-微管蛋白异二聚体之间的界面，与秋水仙碱结合位点重叠。我们的体内致癌模型进一步表明，STK 899704在预防和消退肿瘤方面均有效，通过STK899704治疗可显著减少皮肤肿瘤的数量和体积。此外，值得注意的是，STK899704的疗效惊人地与广泛使用的抗癌治疗药物5-氟尿嘧啶相当。因此，我们的结果证明了STK899704有潜力被开发成为一种抗癌化疗药物以及现有疗法的替代候选药物。
