Dovitinib enhances temozolomide efficacy in glioblastoma cells

Molecular Oncology
Thatchawan ThanasupawatSabine Hombach-Klonisch

Abstract

The multikinase inhibitor and FDA-approved drug dovitinib (Dov) crosses the blood-brain barrier and was recently used as single drug application in clinical trials for GB patients with recurrent disease. The Dov-mediated molecular mechanisms in GB cells are unknown. We used GB patient cells and cell lines to show that Dov downregulated the stem cell protein Lin28 and its target high-mobility group protein A2 (HMGA2). The Dov-induced reduction in pSTAT3Tyr705 phosphorylation demonstrated that Dov negatively affects the STAT3/LIN28/Let-7/HMGA2 regulatory axis in GB cells. Consistent with the known function of LIN28 and HMGA2 in GB self-renewal, Dov reduced GB tumor sphere formation. Dov treatment also caused the downregulation of key base excision repair factors and O6 -methylguanine-DNA-methyltransferase (MGMT), which are known to have important roles in the repair of temozolomide (TMZ)-induced alkylating DNA damage. Combined Dov/TMZ treatment enhanced TMZ-induced DNA damage as quantified by nuclear γH2AX foci and comet assays, and increased GB cell apoptosis. Pretreatment of GB cells with Dov ('Dov priming') prior to TMZ treatment reduced GB cell viability independent of p53 status. Sequential treatment involving 'Dov priming' ...Continue Reading

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Citations

Jun 28, 2018·Molecular Oncology·Thatchawan ThanasupawatThomas Klonisch
Oct 29, 2018·Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research·Shahla ShojaeiSaeid Ghavami
Jun 27, 2019·Journal of Cellular Physiology·Behzad MansooriBehzad Baradaran
Mar 20, 2020·Journal of Drug Targeting·Senthilkumar KalimuthuByeong-Cheol Ahn
Nov 13, 2018·Cell Death Discovery·Adel Rezaei MoghadamJoseph W Gordon
Dec 30, 2020·BMJ Case Reports·Daniele BarbaroLiborio Torregrossa
May 1, 2021·Cancers·Elisabete Cruz Da SilvaLaurence Choulier

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Methods Mentioned

BETA
PCR
xenograft
xenografts
Assay
flow cytometry
FACS

Clinical Trials Mentioned

NCT01972750
NCT01753713

Software Mentioned

Comet Assay IV
cBioPortal

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