Yue-Yu Gu1, Meng-Hua Chen2, Brian H May3, Xiao-Zhong Liao4, Jia-Hui Liu5, Lan-Ting Tao6, Daniel Man-Yuen Sze7, Anthony Lin Zhang8, Sui-Lin Mo9. 1. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China; The Second Clinical College, Guangzhou University of Chinese Medicine and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong Province, China. Electronic address: guyy3@mail2.sysu.edu.cn. 2. School of Health and Biomedical Science, RMIT University, Melbourne, Australia. Electronic address: s3158176@student.rmit.edu.au. 3. School of Health and Biomedical Science, RMIT University, Melbourne, Australia. Electronic address: brian.may@rmit.edu.au. 4. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: liaoxz3@mail2.sysu.edu.cn. 5. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: liujiah23@mail.sysu.edu.cn. 6. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: taolt3@mail2.sysu.edu.cn. 7. School of Health and Biomedical Science, RMIT University, Melbourne, Australia. Electronic address: daniel.sze@rmit.edu.au. 8. School of Health and Biomedical Science, RMIT University, Melbourne, Australia. Electronic address: tony.zhang@rmit.edu.au. 9. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: mosuilin@mail.sysu.edu.cn.
Abstract
BACKGROUND: The World Health Organization (WHO) reported that colorectal cancer (CRC) was the third most common cancer in men and the second in women, worldwide. Our previous meta-analysis found Sophora flavescens increased tumour response rate in randomised controlled trials of CRC. We hypothesised that its principal constituent matrine had exerted anti-tumour effects. PURPOSE: To elucidate its mechanisms of action we investigated the dose-related anti-tumour effects of matrine on four human CRC cell-lines: LS174T, Caco-2, SW1116 and RKO. In a LS174T xenografted tumour model in nude mice we assessed the effects of matrine and oxaliplatin on tumour volume, weight and morphology. Computer simulated dockings for target proteins were also conducted. METHODS AND DESIGN: Cell viability, cell cycle and apoptosis were measured by Cell Counting Kit-8 and flow cytometry, and Annexin V-FITC/PI double staining assay respectively. Western blot was performed to examine the expression of Bax, Bcl-2 and caspase-3 in the cells. The xenograft model and immunohistochemistry were used to investigate the effect of matrine in vivo. Oxaliplatin was set as positive control. Molecular docking was performed to predict the binding modes of matrine and oxaliplatin with target proteins using CDOCKER algorithm. RESULTS: Matrine inhibited proliferation of cancer cells in a dose- and time-dependent manner. Matrine induced cell-cycle arrest at G1/G0 phase, induced apoptosis and reduced expression of Bcl-2 and caspase-3 while up-regulating Bax and cleaved caspase-3 in the four CRC cells. In vivo, matrine significantly inhibited tumour growth without side effects on physical health compared to the negative (vehicle) control group. Mice in the oxaliplatin group lost vigour, became frail and lost weight. Expression of Bcl-2 in tumour tissue was lower and Bax expression was higher in the matrine-treated groups compared to the negative control. In computer-simulated docking, matrine successfully docked into active sites of Bcl-2 and caspase-3. CONCLUSION: Matrine inhibited growth of colorectal cancer cells in vitro and in vivo. A molecular mechanism was apoptosis induction via effects on Bcl-2, Bax and caspase-3. Moreover, matrine showed minimum side effects and may provide a candidate for the development of new therapies for colorectal cancer.
BACKGROUND: The World Health Organization (WHO) reported that colorectal cancer (CRC) was the third most common cancer in men and the second in women, worldwide. Our previous meta-analysis found Sophora flavescens increased tumour response rate in randomised controlled trials of CRC. We hypothesised that its principal constituent matrine had exerted anti-tumour effects. PURPOSE: To elucidate its mechanisms of action we investigated the dose-related anti-tumour effects of matrine on four human CRC cell-lines: LS174T, Caco-2, SW1116 and RKO. In a LS174T xenografted tumour model in nude mice we assessed the effects of matrine and oxaliplatin on tumour volume, weight and morphology. Computer simulated dockings for target proteins were also conducted. METHODS AND DESIGN: Cell viability, cell cycle and apoptosis were measured by Cell Counting Kit-8 and flow cytometry, and Annexin V-FITC/PI double staining assay respectively. Western blot was performed to examine the expression of Bax, Bcl-2 and caspase-3 in the cells. The xenograft model and immunohistochemistry were used to investigate the effect of matrine in vivo. Oxaliplatin was set as positive control. Molecular docking was performed to predict the binding modes of matrine and oxaliplatin with target proteins using CDOCKER algorithm. RESULTS: Matrine inhibited proliferation of cancer cells in a dose- and time-dependent manner. Matrine induced cell-cycle arrest at G1/G0 phase, induced apoptosis and reduced expression of Bcl-2 and caspase-3 while up-regulating Bax and cleaved caspase-3 in the four CRC cells. In vivo, matrine significantly inhibited tumour growth without side effects on physical health compared to the negative (vehicle) control group. Mice in the oxaliplatin group lost vigour, became frail and lost weight. Expression of Bcl-2 in tumour tissue was lower and Bax expression was higher in the matrine-treated groups compared to the negative control. In computer-simulated docking, matrine successfully docked into active sites of Bcl-2 and caspase-3. CONCLUSION: Matrine inhibited growth of colorectal cancer cells in vitro and in vivo. A molecular mechanism was apoptosis induction via effects on Bcl-2, Bax and caspase-3. Moreover, matrine showed minimum side effects and may provide a candidate for the development of new therapies for colorectal cancer.
Authors: Bin Han; Ke Xu; Dan Feng; Yang Bai; Yangqi Liu; Yuanyuan Zhang; Liming Zhou Journal: J Cancer Res Clin Oncol Date: 2022-04-27 Impact factor: 4.322