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Article

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

1
Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia
2
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova, Moscow 119991, Russia
3
Institute of Biomedical Chemistry, Pogodinskaya str., 10, bldg. 8, Moscow 119121, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(9), 2519; https://doi.org/10.3390/ijms19092519
Received: 20 July 2018 / Revised: 14 August 2018 / Accepted: 21 August 2018 / Published: 25 August 2018
(This article belongs to the Special Issue Molecular Chaperones)
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 separators in cancer therapy. View Full-Text
Keywords: Hsp70; Caspase-3; apoptosis; anti-cancer drugs; biological activity prediction; PASS Hsp70; Caspase-3; apoptosis; anti-cancer drugs; biological activity prediction; PASS
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MDPI and ACS Style

Sverchinsky, D.V.; Nikotina, A.D.; Komarova, E.Y.; Mikhaylova, E.R.; Aksenov, N.D.; Lazarev, V.F.; Mitkevich, V.A.; Suezov, R.; Druzhilovskiy, D.S.; Poroikov, V.V.; Margulis, B.A.; Guzhova, I.V. Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3. Int. J. Mol. Sci. 2018, 19, 2519. https://doi.org/10.3390/ijms19092519

AMA Style

Sverchinsky DV, Nikotina AD, Komarova EY, Mikhaylova ER, Aksenov ND, Lazarev VF, Mitkevich VA, Suezov R, Druzhilovskiy DS, Poroikov VV, Margulis BA, Guzhova IV. Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3. International Journal of Molecular Sciences. 2018; 19(9):2519. https://doi.org/10.3390/ijms19092519

Chicago/Turabian Style

Sverchinsky, Dmitry V., Alina D. Nikotina, Elena Y. Komarova, Elena R. Mikhaylova, Nikolay D. Aksenov, Vladimir F. Lazarev, Vladimir A. Mitkevich, Roman Suezov, Dmitry S. Druzhilovskiy, Vladimir V. Poroikov, Boris A. Margulis, and Irina V. Guzhova 2018. "Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3" International Journal of Molecular Sciences 19, no. 9: 2519. https://doi.org/10.3390/ijms19092519

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