title: Resveratrol Increases Anti-Proliferative Activity of Bestatin Through Downregulating P-Glycoprotein Expression Via Inhibiting PI3K/Akt/mTOR Pathway in K562/ADR Cells.
abstract: Multidrug resistance (MDR) is a major obstacle in the clinical therapy of hematological malignancies. P-glycoprotein (P-gp) overexpression results in reduction of intracellular drug concentration with a consequence that the cytotoxicity of anti-tumor drugs is decreased, which leads to MDR in K562/ADR cells. In this study, we found that resveratrol enhanced the anti-proliferative activity of bestatin in K562/ADR cells. Co-treatment with resveratrol, IC50 values of bestatin in K562/ADR cells significantly decreased and activation of caspase-3 and caspase-8 increased, which indicated that resveratrol potentiated bestatin-induced apoptosis. Resveratrol increased the intracellular concentration of bestatin through inhibiting P-gp function and downregulating P-gp expression at mRNA and protein levels, which increased anti-proliferative activity of bestatin in K562/ADR cells. Resveratrol decreased the phosphorylation of Akt and mTOR but did not affect the phosphorylations of JNK or ERK1/2. These results demonstrated that resveratrol could increase the anti-proliferative activity of bestatin through downregulating P-gp expression via suppressing the PI3K/Akt/mTOR signaling pathway.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Shu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D020169:Caspases; D004317:Doxorubicin; D007930:Leucine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C012211:ubenimex
keywords: BESTATIN; CASPASE-3; P-GLYCOPROTEIN; PI3K/AKT/mTOR; RESVERATROL