Enhanced anticancer effect of gemcitabine by genistein in osteosarcoma: the role of Akt and nuclear factor-kappaB.
Genistein, a nontoxic flavonoid compound, has potent antitumor activity in various cancer cell lines. This study was designed to investigate whether combination therapy with gemcitabine and genistein enhances antitumor efficacy in osteosarcoma cell lines (MG-63 and U2OS). Our results show that significant reduction in cell viability and corresponding induction of apoptosis were observed with combination treatment in both cell lines. On the molecular level, we found that gemcitabine alone can activate nuclear factor kappaB (NF-kappaB) in osteosarcoma, suggesting the potential mechanism of acquired chemoresistance. In contrast, genistein reversed the cancer's resistance to gemcitabine through the downregulation of NF-kappaB activity and the suppression of Akt. These findings suggest that the combination of gemcitabine and genistein enhanced the antitumor efficacy by abrogating the Akt/NF-kappaB pathway. The marked ability to induce apoptosis with a combination of gemcitabine and genistein suggests that this could be a rational and novel approach for osteosarcoma preclinical and clinical trials.
Zhang
Bo
B
Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
Shi
Zhong-Li
ZL
Liu
Bing
B
Yan
Xiao-Bo
XB
Feng
Jie
J
Tao
Hui-Min
HM
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D024221:Antineoplastic Protocols; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D019833:Genistein / Q000627:therapeutic use*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; D003841:Deoxycytidine; D019833:Genistein; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine