Email this page

Print this page

Report

Anti-malaria drug blocks proteotoxic stress response: Anti-cancer implications

Nickolay Neznanov, Anton V. Gorbachev, Lubov Neznanova, Andrei P. Komarov, Katerina V. Gurova, Alexander V. Gasparian, Amiya K. Banerjee, Alexandru Almasan, Robert L. Fairchild and Andrei V. Gudkov

The number of physical conditions and chemical agents induce accumulation of misfolded proteins creating proteotoxic stress. This leads to activation of adaptive pro-survival pathway, known as heat shock response (HSR), resulting in expression of additional chaperones. Several cancer treatment approaches, such as proteasome inhibitor Bortezomib and hsp90 inhibitor geldanamycin, involve activation of proteotoxic stress. Low efficacy of these therapies is likely due to the protective effects of HSR induced in treated cells, making this pathway an attractive target for pharmacological suppression. We found that the anti-malaria drugs quinacrine (QC) and emetine prevented HSR in cancer cells, as judged by induction of hsp70 expression. As opposed to emetine, which inhibited general translation, QC did not affect protein synthesis, but rather suppressed inducible HSF1-dependent transcription of the hsp70 gene in a relatively selective manner. The treatment of tumor cells in vitro with a combination of non-toxic concentrations of QC and proteotoxic stress inducers resulted in rapid induction of apoptosis. The effect was similar if QC was substituted by siRNA against hsp70, suggesting that the HSR inhibitory activity of QC was responsible for cell sensitization to proteotoxic stress inducers. QC was also found to enhance the antitumor efficacy of proteotoxic stress inducers in vivo: combinatorial treatment with 17-DMAG+QC resulted in suppression of tumor growth in two mouse syngeneic models. These results reveal that QC is an inhibitor of HSF1-mediated HSR. As such, this compound has significant clinical potential as an adjuvant in therapeutic strategies aimed at exploiting the cytotoxic potential of proteotoxic stress.

Authors

Nickolay Neznanov

Roswell Park Cancer Institute; Buffalo, NY

Anton V. Gorbachev

Cleveland Clinic; Cleveland, OH

Lubov Neznanova

Roswell Park Cancer Institute; Buffalo, NY

Andrei P. Komarov

Cellecta, Inc.; Mountain View, CA

Katerina V. Gurova

Roswell Park Cancer Institute; Buffalo, NY

Alexander V. Gasparian

Cleveland Biolabs, Inc.; Buffalo, NY

Amiya K. Banerjee

Cleveland Clinic; Cleveland, OH

Alexandru Almasan

Cleveland Clinic; Cleveland, OH

Robert L. Fairchild

Cleveland Clinic; Cleveland, OH

Andrei V. Gudkov Corresponding author: andrei.gudkov@roswellpark.org

Roswell Park Cancer Institute; Buffalo, NY