title: Genistein potentiates the anti-cancer effects of gemcitabine in human osteosarcoma via the downregulation of Akt and nuclear factor-κB pathway.
abstract: Genistein, a nontoxic flavonoid compound, has potent antitumor activity in various cancer cells. In the present study, we investigated whether genistein could be employed as a novel strategy to enhance the anti-tumor activity of gemcitabine using human osteosarcoma MNNG/HOS tumor model. In vitro, by MTT, electron microscopy, immunobloting and qRT-PCR assay, we found that the combination treatment of genistein and gemcitabine resulted in stronger growth inhibition and apoptosis induction through the downregulation of NF-κB activity and Akt activation in osteosarcoma cells. Moreover, the synergetic effects were observed when genistein was replaced by PI3K/Akt-pathway inhibitor (LY-294002) or NF-κB inhibitor (BAY11-7082). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-κB activity and Akt activation in xenografts. Taken together, these results provide in vitro and in vivo evidence that genistein abrogates gemcitabine-induced activation of NF-κB and increases the chemosensitization of osteosarcoma to gemcitabine. Combination therapy appears as a rational and novel approach for osteosarcoma treatment.
authors.affiliation: Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.
authors.forename: Chengzhen
authors.initials: C
authors.lastname: Liang
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Chengchun
authors.initials: C
authors.lastname: Shen
authors.forename: Jianbo
authors.initials: J
authors.lastname: Lai
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Shi
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Hui-min
authors.initials: HM
authors.lastname: Tao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D003841:Deoxycytidine; D019833:Genistein; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine