Jia-Hui Chu1, Cui-Rong Zhao2, Zhi-Yu Song1, Rui-Qi Wang1, Yi-Zhuo Qin1, Wen-Bao Li3, Xian-Jun Qu4. 1. Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. 2. Shandong provincial hospital affiliated to Shandong University, 250021, China. 3. Sanlugen PharmaTech, Rm 506, No. 2766 Yingxiu Road, Jinan 250101, China. Electronic address: wbli92128@163.com. 4. Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. Electronic address: qxj@sdu.edu.cn.
Abstract
PURPOSE: 1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells. METHODS: Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. RESULTS: 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways. CONCLUSIONS: 1082-39 is a promising candidate compound which could develop as a potent anticancer agent.
PURPOSE: 1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against humancancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in humanmelanoma M21 cells. METHODS: Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. RESULTS: 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways. CONCLUSIONS: 1082-39 is a promising candidate compound which could develop as a potent anticancer agent.