title: Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via downregulation of HIF-1α and glycolysis, by inhibiting PI3K/Akt signaling pathway.
abstract: Hypoxia induced drug resistance is a major obstacle in the development of effective cancer therapy. In the present study, the reversal abilities of wogonin on the hypoxia resistance and the underlying mechanisms were discovered. MTT assay revealed that hypoxia increased maximal 1.71-, 2.08-, and 2.15-fold of IC50 toward paclitaxel, ADM, and DDP in human colon cancer cell lines HCT116, respectively. Furthermore, wogonin showed strong reversal potency in HCT116 cells in hypoxia and the RF reached 2.05. hypoxia-inducible factor-1α (HIF-1α) can activate the expression of target genes involved in glycolysis. Wogonin decreased the expression of glycolysis-related proteins (HKII, PDHK1, LDHA), glucose uptake, and lactate generation in a dose-dependent manner. Further, Western blot experiments exhibited that wogonin could down regulate HIF-1α expression and glycolysis through inhibiting PI3K/Akt signaling pathway, which might be the mechanism of reversal resistance of wogonin. Also, wogonin could inhibit the growth of transplantable tumors and the expression of HIF-1α, glycolysis-related proteins and PI3K/Akt in vivo. In summary, wogonin could be a good candidate for the development of new multidrug resistance (MDR) reversal agent and its reversal mechanism probably is due to the suppression of HIF-1α expression via inhibiting PI3K/Akt signaling pathway.
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Li-Tao
authors.initials: LT
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Di
authors.initials: D
authors.lastname: Pan
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology*; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007773:Lactates / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D004365:Drugs, Chinese Herbal; D044950:Flavanones; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C497442:HIF1A protein, human; C085514:wogonin
keywords: HIF-1α; hypoxia; reversal effect; wogonin