Bigelovin triggered apoptosis in colorectal cancer in vitro and in vivo via upregulating death receptor 5 and reactive oxidative species.
Colorectal cancer (CRC) is the third most prevalent cancer and the third highest cancer-related mortality in the United States. Bigelovin, a sesquiterpene lactone isolated from Inula helianthus aquatica, has been proven to induce apoptosis and exhibit anti-inflammatory and anti-angiogenic activities. However, the effects of bigelovin on CRC and underlying mechanisms have not been explored. The present study demonstrated that bigelovin exhibited potent anti-tumor activities against CRC in vitro and in vivo. Bigelovin suppressed cell proliferation and colony formation and induced apoptosis in human colorectal cancer HT-29 and HCT 116 cells in vitro. Results also revealed that bigelovin activated caspases, caused the G2/M cell cycle arrest and induced DNA damage through up-regulation of death receptor (DR) 5 and increase of ROS. In HCT 116 xenograft model, bigelovin treatment resulted in suppression of tumor growth. Bigelovin at 20 mg/kg showed more significant tumor suppression and less side effects than conventional FOLFOX (containing folinic acid, 5-fluorouracil and oxaliplatin) treatment. In addition, in vivo data confirmed that anti-tumor activity of bigelovin in CRC was through induction of apoptosis by up-regulating DR5 and increasing ROS. In conclusion, these results strongly suggested that bigelovin has potential to be developed as therapeutic agent for CRC patients.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Mingyue
M
Li
School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing 211198, China.
Li-Hua
LH
Song
Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Grace Gar-Lee
GG
Yue
Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Julia Kin-Ming
JK
Lee
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Li-Mei
LM
Zhao
Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Lin
L
Li
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Xunian
X
Zhou
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Stephen Kwok-Wing
SK
Tsui
Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Simon Siu-Man
SS
Ng
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Kwok-Pui
KP
Fung
School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing 211198, China.|State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Ning-Hua
NH
Tan
Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin New Territories, Hong Kong.
Clara Bik-San
CB
Lau
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D012717:Sesquiterpenes / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D012717:Sesquiterpenes; C505639:TNFRSF10B protein, human; C099796:bigelovin