title: Rosiglitazone elevates sensitization of drug-resistant oral epidermoid carcinoma cells to vincristine by G2/M-phase arrest, independent of PPAR-γ pathway.
abstract: Rosiglitazone (ROSI), an oral antidiabetic agent, has been reported the anti-cancer properties recent years. In this paper, the potency of ROSI as a synergistic drug for vincristine (VCR) on resistant oral cancer cells was investigated. We found that ROSI potently enhanced the susceptibility of KB cells or KB/V cells to VCR in a dose manner and the synergy in KB/V cells was much more prominent than that in KB cells. The synergistic anti-proliferative effect of ROSI and VCR was associated with inhibition on tubulin polymerization, cell cycle arrest in G2/M phase and cell apoptosis induction, but has no effect on drug efflux-protein P-gp and was independent with PPARγ. The combination treatment of ROSI and VCR could regulate the PTEN/PI3K/AKT survival pathway with an upregulation of PTEN and down-regulation of p-AKT. The effect of G2/M phase arrest was associated with the upregulation of cyclin B1 and downregulation of p-cdc2. The apoptosis induction of ROSI and VCR was partly due to an upregulation of cleaved PARP and downregulation of Bcl-2/Bax ratio. In addition, combination treatment of ROSI and VCR had also shown anti-angiogenic effect by suppressing the migration and blocking the capillary tube formation of HUVECs. More importantly, this combination treatment induced an acceptably weak cytotoxicity in human normal HL-7702 cells, GES-1 cells and HUVECs. Taken together, ROSI may be used as a potential compound for combinatorial therapy or as a complement to VCR for treatment on oral cancer, especially on that have acquired resistance to VCR therapy.
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
authors.forename: Yu-Yin
authors.initials: YY
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xin
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China. Electronic address: guoxl@sdu.edu.cn.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Guo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D009062:Mouth Neoplasms / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056744:Cyclin B1; D047495:PPAR gamma; D045162:Thiazolidinediones; D014404:Tubulin; D051028:bcl-2-Associated X Protein; D000077154:Rosiglitazone; D014750:Vincristine; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
keywords: Cell cycle; Cell proliferation and apoptosis; Drug resistance reversal; Oral epidermoid carcinoma; PTEN/PI3K/AKT; Rosiglitazone; Vincristine