Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongju 28116, Korea.
Department of Biomolecular Science, University of Science and Technology, Daejeon 34113, Korea.
Int J Mol Sci. 2020 Jul 7;21(13):4800. doi: 10.3390/ijms21134800.
In the past, several microtubule targeting agents (MTAs) have been developed into successful anticancer drugs. However, the usage of these drugs has been limited by the acquisition of drug resistance in many cancers. Therefore, there is a constant demand for the development of new therapeutic drugs. Here we report the discovery of 5-5 (3-cchlorophenyl)-N-(3-pyridinyl)-2-furamide (CPPF), a novel microtubule targeting anticancer agent. Using both 2D and 3D culture systems, we showed that CPPF was able to suppress the proliferation of diverse cancer cell lines. In addition, CPPF was able to inhibit the growth of multidrug-resistant cell lines that are resistant to other MTAs, such as paclitaxel and colchicine. Our results showed that CPPF inhibited growth by depolymerizing microtubules leading to mitotic arrest and apoptosis. We also confirmed CPPF anticancer effects in vivo using both a mouse xenograft and a two-step skin cancer mouse model. Using established zebrafish models, we showed that CPPF has low toxicity in vivo. Overall, our study proves that CPPF has the potential to become a successful anticancer chemotherapeutic drug.
过去，已有几种微管靶向剂（MTAs）被开发为成功的抗癌药物。然而，由于许多癌症中出现了耐药性的获得，这些药物的使用受到了限制。因此，不断需要开发新的治疗药物。在这里，我们报告了一种新型微管靶向抗癌剂 5-5（3-氯苯基）-N-（3-吡啶基）-2-呋喃甲酰胺（CPPF）的发现。我们使用 2D 和 3D 培养系统表明，CPPF 能够抑制多种癌细胞系的增殖。此外，CPPF 能够抑制对其他 MTAs（如紫杉醇和秋水仙碱）耐药的多药耐药细胞系的生长。我们的结果表明，CPPF 通过解聚微管导致有丝分裂停滞和细胞凋亡来抑制生长。我们还通过使用小鼠异种移植和两步皮肤癌小鼠模型在体内证实了 CPPF 的抗癌作用。使用已建立的斑马鱼模型，我们表明 CPPF 在体内的毒性较低。总的来说，我们的研究证明 CPPF 有可能成为一种成功的抗癌化疗药物。
