In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma

Chiao-En Wu, Chiao-Ping Chen, Yi-Ru Pan, Shih-Ming Jung, John Wen-Cheng Chang, Jen-Shi Chen, Chun-Nan Yeh, John Lunec

Research output: Contribution to journalJournal Article peer-review

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second highest incidence of primary liver cancers after hepatocellular carcinoma. The lack of ef-fective treatment leads to a poor prognosis for advanced iCCA, so new targeted therapy is needed. The impairment of wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Combining an MDM2 inhibitor (MDM2i, RG7388) to stabilize p53 and a WIP1 inhibitor (WIP1i, GSK2830371) to increase p53 phosphorylation enhances p53 function. The combination of MDM2 and WIP1 inhib-itors has been reported in several cancer types but in vivo studies are lacking. In the current study, liver adenocar-cinoma cell lines, RBE and SK-Hep-1, were treated with RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, SK-Hep-1 xenografts in NOD-SCID mice were treated with combination therapy for two weeks. The combi-nation of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxicty, p53 protein expression, and phosphorylation (Ser15), leading to transactivation of downstream targets (p21WAF1 and MDM2). The in vivo results demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, the liver adeno-carcinoma cell lines responded to combination treatment via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and expression of its downstream targets. This efficacy was also demonstrated in vivo. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma that warrants further investigation.
Original languageAmerican English
Pages (from-to)4399
JournalAmerican Journal of Cancer Research
Volume12
Issue number9
StatePublished - 2022

Keywords

  • BILIARY-TRACT CANCERS
  • GSK2830371
  • HEPATECTOMY
  • INHIBITION
  • MDM2
  • MDM2
  • P53
  • RG7388
  • SURVIVAL
  • THERAPY
  • WIP1
  • WIP1
  • cholangiocarcinoma
  • p53

Fingerprint

Dive into the research topics of 'In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma'. Together they form a unique fingerprint.

Cite this