HDAC inhibitors enhance the lethality of low dose salinomycin in parental and stem-like GBM cells

Cancer Biology & Therapy
Laurence BoothPaul Dent

Abstract

The present studies determined whether the antibiotic salinomycin interacted with HDAC inhibitors to kill primary human GBM cells. Regardless of PTEN, ERBB1, or p53 mutational status salinomycin interacted with HDAC inhibitors in a synergistic fashion to kill GBM cells. Inhibition of CD95/Caspase 8 or of CD95/RIP-1/AIF signaling suppressed killing by the drug combination. Salinomycin increased the levels of autophagosomes that correlated with increased p62 and LC3II levels; valproate co-treatment correlated with reduced LC3II and p62 expression, and increased caspase 3 cleavage. Molecular inhibition of autophagosome formation was protective against drug exposure. The drug combination enhanced eIF2α phosphorylation and decreased expression of MCL-1 and phosphorylation of mTOR and p70 S6K. Activation of p70 S6K or mTOR promoted cell survival in the face of combined drug exposure. Overexpression of BCL-XL or c-FLIP-s was protective. Collectively our data demonstrate that the lethality of low nanomolar concentrations of salinomycin are enhanced by HDAC inhibitors in GBM cells and that increased death receptor signaling together with reduced mitochondrial function are causal in the combinatorial drug necro-apoptotic killing effect.

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Citations

Dec 9, 2014·Cancer Biology & Therapy·Laurence BoothPaul Dent
Mar 12, 2016·Nature Reviews. Neurology·Gilles Huberfeld, Charles J Vecht
Feb 18, 2015·DNA and Cell Biology·Laurence BoothPaul Dent
Jun 22, 2016·ACS Medicinal Chemistry Letters·Björn BorgströmDaniel Strand
Oct 11, 2017·Neuro-oncology·Evanthia GalanisUNKNOWN Alliance for Clinical Trials in Oncology and ABTC
Sep 11, 2016·Oncotarget·Gary D R RoulstonAlexander Thompson
Dec 30, 2014·Journal of Cellular Physiology·Laurence BoothPaul Dent
Dec 12, 2018·Scientific Reports·Aistė SkeberdytėSonata Jarmalaitė
Jul 9, 2020·Cancer Chemotherapy and Pharmacology·R Gajendra ReddyArvind Kumar
Aug 3, 2017·International Journal of Oncology·Justin W Magrath, Yonghyun Kim
Aug 12, 2014·Molecular Cancer Therapeutics·Laurence BoothPaul Dent
Jan 6, 2019·European Journal of Medicinal Chemistry·Michał Antoszczak
Dec 31, 2020·Cancers·Elia BozzatoVéronique Préat
Jun 9, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yi WangBo Liu

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