Identification of the atypical antipsychotic Asenapine as a direct survivin inhibitor with anticancer properties and sensitizing effects to conventional therapies

Abstract

Therapy resistance in human cancers is a major limitation in Clinical Oncology. In this regard, overexpression of anti-apoptotic proteins, such as survivin, has been described in several tumors, contributing to this clinical issue. Survivin has a dual role in key cellular functions, inducing cell cycle progression and inhibiting apoptosis; thus, survivin is an attractive target for cancer therapy. Therefore, we focused on identifying and validating a novel specific, directly binding survivin inhibitor for cancer treatment and tumor sensitization to conventional proapoptotic therapies. In this work, we conducted a structure-based high-throughput virtual screening at the survivin homodimerization domain. Asenapine Maleate (AM), an approved drug for central nervous system diseases, was identified as a direct binder of the survivin homodimerization domain and it significantly affected cell viability of lung, colon, and brain cancer cell lines. Direct interaction of AM to survivin protein was corroborated by surface plasmon resonance and a specific survivin protein decrease was observed in cancer cells, compared to other inhibitors of apoptosis proteins. Therapeutic in vivo studies showed an impairment of tumor growth in AM-treated mice. Finally, a synergistic anticancer effect was detected in vitro when combined with different conventional chemotherapies, and in vivo studies showed higher antitumor effects when combined with cisplatin. Altogether, our results identify AM as a specific direct binding inhibitor of survivin, showing anticancer properties in vitro and in vivo and sensitizing effects when combined with cisplatin, opening the possibility of repositioning this approved drug for cancer treatment.

Keywords: Combination treatment; Drug repositioning; Inhibitor of apoptosis proteins; Lung cancer; Survivin inhibitor; Treatment sensitization.