title: Resistance of SMMC-7721 hepatoma cells to etoposide in hypoxia is reversed by VEGF inhibitor.
abstract: Hypoxia is associated with resistance to chemotherapy in a number of human cancer types; particularly in hepatocellular carcinoma (HCC), which is a highly vascularized tumor. To develop a potential combination therapy strategy that is capable of overcoming the hypoxia‑induced insensitivity to chemotherapy, the HCC cell SMMC‑7721 was employed to investigate the hypoxia‑induced chemoresistance to etoposide. Increased levels of hypoxia‑inducible factor‑1α (HIF‑1α) and vascular endothelial growth factor (VEGF) were observed when SMMC‑7721 cells were exposed to hypoxia, and exposure of tumor cells to hypoxia impaired etoposide‑induced DNA damage, as indicated by the failure of upregulation of γHA2X. Etoposide‑induced apoptosis and cell cycle arrest of SMMC‑7721 was also impaired in hypoxia. However, co‑treatment with anti‑VEGF significantly restored etoposide‑induced cell apoptosis and cell cycle arrest, as indicated by the elimination of B‑cell lymphoma 2 (Bcl‑2), procaspase 3, cyclin B1 and Cdc2. Furthermore, anti‑VEGF eliminated phosphorylation of AKT, ERK and IκB‑α resulting from hypoxia, suggesting the involvement of VEGF in the activation of the survival pathways. In conclusion, the present study suggests a significant role of VEGF in the chemoresistance of etoposide in hypoxia. A rational chemotherapy should be developed based on a combination of etoposide and anti‑VEGF.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Shi
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Chenxing
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Pharmacy, Fenghua Hospital, Ningbo, Zhejiang 315040, P.R. China.
authors.forename: Kaizan
authors.initials: K
authors.lastname: Zhuang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Guikai
authors.initials: G
authors.lastname: Liang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Zhangting
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Duoduo
authors.initials: D
authors.lastname: Wang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Weng
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Cao
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Peihua
authors.initials: P
authors.lastname: Luo
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Pharmacy, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310009, P.R. China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Ma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases