Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation.
Colorectal cancer (CRC) is still the third most common cancer and the second most common causes of cancer-related death around the world. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been shown to have a suppressive effect on CRC risk and mortality, but not all laboratory studies suggest that metformin has antineoplastic activity. Here, we investigated the effect of metformin and AMPK activator AICAR on CRC cells proliferation. As a result, metformin did not inhibit cell proliferation or induce apoptosis for CRC cell lines in vitro and in vivo. Different from metformin, AICAR emerged antitumor activity and sensitized anticancer effect of 5-FU on CRC cells in vitro and in vivo. In further analysis, we show that AMPK activation may be a key molecular mechanism for the additive effect of AICAR. Taken together, our results suggest that metformin has not antineoplastic activity for CRC cells as a single agent but AMPK activator AICAR can induce apoptosis and enhance the cytotoxic effect of 5-FU through AMPK activation.
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Xinbing
X
Sui
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Yinghua
Y
Xu
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Jie
J
Yang
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Yong
Y
Fang
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Haizhou
H
Lou
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Weidong
W
Han
Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Maolin
M
Zhang
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Wei
W
Chen
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Kaifeng
K
Wang
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Da
D
Li
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Wei
W
Jin
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Fang
F
Lou
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Yu
Y
Zheng
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Hong
H
Hu
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Liu
L
Gong
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Xiaoyun
X
Zhou
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Qin
Q
Pan
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Hongming
H
Pan
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Xian
X
Wang
Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Chao
C
He
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D012265:Ribonucleotides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D020536:Enzyme Activators; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005472:Fluorouracil