Methyl Sartortuoate Inhibits Colon Cancer Cell Growth by Inducing Apoptosis and G2/M-Phase Arrest.
The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. lansysu@foxmail.com.
Qiusheng
Q
Lan
Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou 350000, China. jesmy@126.com.
Shoufeng
S
Li
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. weilaiv2001@126.com.
Wei
W
Lai
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. xuheyang2012@126.com.
Heyang
H
Xu
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. sumsyorky@hotmail.com.
Yang
Y
Zhang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. sumsyorky@hotmail.com.
Yujie
Y
Zeng
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Wenjian
W
Lan
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. sumschuzhonghua@hotmail.com.
Zhonghua
Z
Chu
D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000302:isolation & purification / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D013729:Terpenes; C000607798:methyl sartortuoate; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
G2-M arrest; MAPK; apoptosis; colon cancer; methyl sartortuoate