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Article

Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach

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Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco, (UPV/EHU), Barrio Sarriena, 48940 Leioa, Spain
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Departamento de Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco, (UPV/EHU), Barrio Sarriena, 48940 Leioa, Spain
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Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
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Department of Chemistry, University of Bergen, Allégaten 41, 5007 Bergen, Norway
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Departament de Química, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
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Departamento de Biología Celular e Histología, Facultad de Medicina y Enfermería, Universidad del País Vasco, (UPV/EHU), Barrio Sarriena, 48940 Leioa, Spain
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Instituto de Investigación Biocruces Bizkaia, Hospital Universitario Cruces, 48903 Barakaldo, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Mitsuru Okuwaki
Cancers 2021, 13(12), 2936; https://doi.org/10.3390/cancers13122936
Received: 28 May 2021 / Accepted: 8 June 2021 / Published: 11 June 2021
(This article belongs to the Section Molecular Cancer Biology)
High levels of Heat shock proteins (Hsps) in specific cancers are usually linked to a poor prognosis, tumor progression, invasiveness, and resistance to treatment. Chaperone inhibition could therefore be toxic for cancer cells due to their high dependence on chaperone activity to survive. This study shows the potential to repurpose the small chemical compound pinaverium bromide, currently used to treat functional gastrointestinal disorders, as a possible antitumor drug since it displays a marked toxicity against two melanoma cell lines without affecting the viability of fibroblast and primary melanocytes. This compound interacts with structural regions shared by representatives of the Hsp70 and Hsp110 families, inhibiting the substrate remodeling ability of the Hsp70 system in vitro and in a cellular context.
Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach. View Full-Text
Keywords: chaperones; drug repurposing; inhibitors; melanoma; pinaverium bromide chaperones; drug repurposing; inhibitors; melanoma; pinaverium bromide
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MDPI and ACS Style

Dublang, L.; Underhaug, J.; Flydal, M.I.; Velasco-Carneros, L.; Maréchal, J.-D.; Moro, F.; Boyano, M.D.; Martinez, A.; Muga, A. Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach. Cancers 2021, 13, 2936. https://doi.org/10.3390/cancers13122936

AMA Style

Dublang L, Underhaug J, Flydal MI, Velasco-Carneros L, Maréchal J-D, Moro F, Boyano MD, Martinez A, Muga A. Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach. Cancers. 2021; 13(12):2936. https://doi.org/10.3390/cancers13122936

Chicago/Turabian Style

Dublang, Leire, Jarl Underhaug, Marte I. Flydal, Lorea Velasco-Carneros, Jean-Didier Maréchal, Fernando Moro, Maria D. Boyano, Aurora Martinez, and Arturo Muga. 2021. "Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach" Cancers 13, no. 12: 2936. https://doi.org/10.3390/cancers13122936

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