Antitumor effect of manumycin on colorectal cancer cells by increasing the reactive oxygen species production and blocking PI3K-AKT pathway.
Manumycin is a natural, well-tolerated microbial metabolite and is regarded as a farnesyltransferase inhibitor. Some data suggest that manumycin inhibits proliferation of diverse cancer cells through various pathways. However, the antitumor effect of manumycin on colorectal cancer (CRC) remains unknown. In the present study, we investigated the antitumor effect of manumycin on CRC in vitro and in vivo. The results of cell viability assay revealed that the proliferation of the CRC cells was significantly inhibited by manumycin. Moreover, cell apoptosis induced by manumycin was also found in a time- and dose-dependent manner. Interestingly, treatment of the CRC cells with manumycin resulted in increased generation of reactive oxygen species. Subsequently, manumycin also decreased the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT, as well as the expression of caspase-9 and poly(ADP-ribose) polymerase (PARP) in a time-dependent manner. In addition, we found that N-acetyl-l-cysteine (NAC) attenuated the effect of manumycin on the PI3K-AKT pathway, and wortmannin reduced the effect of manumycin on caspase-9 and PARP expression. More importantly, the anticancer effect of manumycin was also observed in established tumor xenografts. Taken together, these findings supported the potential application of manumycin against colorectal carcinoma.
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Jingyu
J
Zhang
Department of Oncology, Affiliated Changzhou No 2 People's Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Hua
H
Jiang
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Li
L
Xie
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Jing
J
Hu
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Li
L
Li
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Mi
M
Yang
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Lei
L
Cheng
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Baorui
B
Liu
Department of the Comprehensive Cancer Center, Affiliated Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Xiaoping
X
Qian
PI3K-AKT pathway; ROS; colorectal cancer; manumycin