Boichuk Sergei, Galembikova Aigul, Zykova Svetlana, Ramazanov Bulat, Khusnutdinov Ramil, Dunaev Pavel, Khaibullina Svetlana, Lombardi Vincent
aDepartment of Pathology, Kazan State Medical University, Kazan bDepartment of Zootechnology, Perm State Academy of Pharmacy, Perm, Russian Federation cNevada Biomedical Research Institute, University of Nevada, Reno, Nevada, USA.
Anticancer Drugs. 2016 Aug;27(7):620-34. doi: 10.1097/CAD.0000000000000372.
Microtubules are known to be one of the most attractive and validated targets in cancer therapy. However, the clinical use of drugs that affect the dynamic state of microtubules has been hindered by chemoresistance and toxicity issues. Accordingly, the development of novel agents that target microtubules is needed. Here, we report the identification of novel compounds with pirrole and carboxylate structures: ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) that provide potent cytotoxic activities against multiple soft tissue cancer cell lines in vitro. Using the MTS cell proliferation assay, we assessed the activity of EAPCs on various cancer cell lines including leiomyosarcoma SK-LMS-1, rhabdomyosarcoma RD, gastrointestinal stromal tumor GIST-T1, A-673 Ewing's sarcoma, and U-2 OS osteosarcoma. We found that in the majority of cases, two EAPC compounds (EAPC-20 and EAPC-24) considerably inhibited cancer cell proliferation in vitro. The growth-inhibitory effects of EAPC-20 and EAPC-24 were time and dose dependent. The molecular mechanisms of action of these compounds were because of the inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to considerable accumulation of tumor cells in the M-phase. Finally, EAPCs induced tumor cell death by apoptotic pathways. The above-mentioned effects were also observed in most soft tissue tumor cell lines and the gastrointestinal stromal tumor cell line investigated. Taken together, our data identify potent antitumor activity of EAPCs in vitro, thus providing a novel scaffold with which to develop potent chemotherapeutic agents for cancer therapy.
微管被认为是癌症治疗中最具吸引力且经过验证的靶点之一。然而，影响微管动态状态的药物在临床应用中受到化疗耐药性和毒性问题的阻碍。因此，需要开发靶向微管的新型药物。在此，我们报告了具有吡咯和羧酸盐结构的新型化合物的鉴定：2-氨基-吡咯-3-羧酸乙酯（EAPCs），其在体外对多种软组织癌细胞系具有强大的细胞毒性活性。使用MTS细胞增殖测定法，我们评估了EAPCs对各种癌细胞系的活性，包括平滑肌肉瘤SK-LMS-1、横纹肌肉瘤RD、胃肠道间质瘤GIST-T1、A-673尤文肉瘤和U-2 OS骨肉瘤。我们发现，在大多数情况下，两种EAPC化合物（EAPC-20和EAPC-24）在体外显著抑制癌细胞增殖。EAPC-20和EAPC-24的生长抑制作用具有时间和剂量依赖性。这些化合物的分子作用机制是由于抑制微管蛋白聚合并诱导强大的G2/M细胞周期阻滞，导致肿瘤细胞在M期大量积累。最后，EAPCs通过凋亡途径诱导肿瘤细胞死亡。在大多数研究的软组织肿瘤细胞系和胃肠道间质瘤细胞系中也观察到了上述效应。综上所述，我们的数据确定了EAPCs在体外具有强大的抗肿瘤活性，从而为开发用于癌症治疗的强效化疗药物提供了一种新型支架。
