Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3

International Journal of Molecular Sciences
Dmitry V SverchinskyIrina Guzhova

Abstract

The Hsp70 chaperone binds and inhibits proteins implicated in apoptotic signaling including Caspase-3. Induction of apoptosis is an important mechanism of anti-cancer drugs, therefore Hsp70 can act as a protective system in tumor cells against therapeutic agents. In this study we present an assessment of candidate compounds that are able to dissociate the complex of Hsp70 with Caspase-3, and thus sensitize cells to drug-induced apoptosis. Using the PASS program for prediction of biological activity we selected a derivative of benzodioxol (BT44) that is known to affect molecular chaperones and caspases. Drug affinity responsive target stability and microscale thermophoresis assays indicated that BT44 bound to Hsp70 and reduced the chaperone activity. When etoposide was administered, heat shock accompanied with an accumulation of Hsp70 led to an inhibition of etoposide-induced apoptosis. The number of apoptotic cells increased following BT44 administration, and forced Caspase-3 processing. Competitive protein⁻protein interaction and immunoprecipitation assays showed that BT44 caused dissociation of the Hsp70⁻Caspase-3 complex, thus augmenting the anti-tumor activity of etoposide and highlighting the potential role of molecular se...Continue Reading

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Citations

May 18, 2020·Journal of Clinical Pharmacy and Therapeutics·Xiang GengYuan Li
Apr 28, 2021·European Journal of Medicinal Chemistry·Ziqian WangZhichao Zhang
Jun 3, 2021·International Journal of Molecular Sciences·Mercedes QuintanaJosé Quintana

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Methods Mentioned

BETA
microscale thermophoresis
interaction assay
immunoprecipitation
electrophoresis
nucleotide-exchange
Assay

Software Mentioned

NanoTemper
CytExpert
PASS
MST
NanoTemper Analysis
PASS ( Prediction of Biological Activity Spectra for Substances )

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