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Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.

ABSTRACT: Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PDGFR-? and its downstream Akt/mTOR and Mek/Erk signaling pathways. Cell death induced by linifanib was greatly enhanced after autophagy inhibition by the pharmacological inhibitors or siRNAs against autophagy related genes, ATG5 and ATG7, in vitro. Moreover, HCQ, an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-HCC effect of linifanib in a mouse xenograft model. In conclusion, linifanib can induce cytoprotective autophagy by suppression of PDGFR-? activities in HCC cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of linifanib in the treatment of HCC patients.

SUBMITTER: Pan H

PROVIDER: S-EPMC4202209 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.

Pan Hongming H Wang Zhanggui Z Jiang Liming L Sui Xinbing X You Liangkun L Shou Jiawei J Jing Zhao Z Xie Jiansheng J Ge Weiting W Cai Xiujun X Huang Wendong W Han Weidong W

Scientific reports 20141020

Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PD ...[more]

PMID: 25327881

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Project description:BackgroundHepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC.MethodsHuman HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114.ResultsDBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group.ConclusionOur results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC.

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Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.

Publications

Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.

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