SKLB316, a novel small-molecule inhibitor of cell-cycle progression, induces G2/M phase arrest and apoptosis in vitro and inhibits tumor growth in vivo
| Autor: | Ningyu Wang, Ying Xiong, Wenshuang Wu, Tao Yin, Yong Xia, Yongxia Zhu, Guo-Bo Li, Yantong Liu, Bin Shao, Luoting Yu, Tinghong Ye, Yuquan Wei, Xuejiao Song, Lifeng Zhao, Xuan-Hong Shi, Qian Lei |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Cell cycle checkpoint Cyclin E Mice Nude Antineoplastic Agents Apoptosis Mice chemistry.chemical_compound Bcl-2-associated X protein Cyclins CDC2 Protein Kinase Animals Humans cdc25 Phosphatases Benzothiazoles Propidium iodide Phosphorylation Cyclin B1 Cell Proliferation bcl-2-Associated X Protein Membrane Potential Mitochondrial Cyclin-dependent kinase 1 biology Cell growth HCT116 Cells Xenograft Model Antitumor Assays Caspase 9 Cell biology G2 Phase Cell Cycle Checkpoints Pancreatic Neoplasms Checkpoint Kinase 2 Oncology chemistry biology.protein Female Colorectal Neoplasms Reactive Oxygen Species |
| Zdroj: | Cancer Letters. 355:297-309 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2014.09.042 |
| Popis: | Benzothiazole derivatives have received considerable attentions for their potencies in cancer therapy. In the present study, we reported that SKLB316, a novel synthesized benzothiazole derivative, exhibits activities to inhibit colorectal and pancreatic cancer in vitro and in vivo by inducing G2/M cell cycle arrest and apoptosis. In vitro, it exhibited significant anti-proliferative activities against human cancer cells derived from different histotypes including the colorectal cancer cell line HCT116 and pancreatic cancer cell line CFPAC-1. We chose these cell lines to study the possible anti-tumor mechanism because they are sensitive to SKLB316 treatment. Flow cytometry assays showed that SKLB316 could induce G2/M cell cycle arrest. Mechanistically, SKLB316 could decrease the activities of cdc2/cyclin B1 complex, including decreasing the synthesis of cyclin B1, cdc2 and cdc25c, while accumulating the levels of phosphorylated cdc2 (Tyr15) and checkpoint kinase 2. SKLB316 could also decrease the level of cyclin E and A2. Moreover, SKLB316 could induce cancer cell apoptosis, which was associated with activation of caspase 9, downregulation of Bcl-2 and upregulation of Bax. SKLB316 could also decrease the mitochondrial membrane potential and induce the generation of reactive oxygen species in cells. The results implied that SKLB316 may induce apoptosis via the mitochondria-mediated apoptotic pathway. Moreover, SKLB316 could suppress the growth of established colorectal and pancreatic cancer tumors in nude mice without causing obvious side effects. TUNEL assays confirmed that SKLB316 could also induce tumor cell apoptosis in vivo. Taken together, these findings demonstrate the potential value of SKLB316 as a novel anti-tumor drug candidate. |
| Databáze: | OpenAIRE |
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