Sertraline repositioning: an overview of its potential use as a chemotherapeutic agent after four decades of tumor reversal studies

Abstract

Sertraline hydrochloride is a first-line antidepressant with potential antineoplastic properties because of its structural similarity with other drugs capable to inhibit the translation-controlled tumor protein (TCTP), a biomolecule involved in cell proliferation. Recent studies suggest it could be repositioned for cancer treatment. In this review, we systematically map the findings that repurpose sertraline as an antitumoral agent, including the mechanisms of action that support this hypotesis. From experimental in vivo and in vitro tumor models of thirteen different types of neoplasms, three mechanisms of action are proposed: apoptosis, autophagy, and drug synergism. The antidepressant is able to inhibit TCTP, modulate chemotherapeutical resistance and exhibit proper cytotoxicity, resulting in reduced cell counting (in vitro) and shrunken tumor masses (in vivo). A mathematical equation determined possible doses to be used in human beings, supporting that sertraline could be explored in clinical trials as a TCTP-inhibitor.

Keywords: Antidepressant agents; Apoptosis; Drug repurposing; Neoplasms; Sertraline; TCTP.

Graphical abstract

Fig. 1

Sertraline-TCTP binding results in apoptosis and tumor reversal. Caption: Antitumoral mechanism of action of sertraline by preventing the degradation of p53 by TCTP and suppression of TCTP leading to tumor reversion. Sertraline binds directly to tpt1/TCTP, avoiding its interaction with MDM2 and, thus, promoting the interaction of TCTP autoubiquitination with MDM2 and p53, leading to MDM2 autoubiquitination and thus, restoring p53 levels. Consequently, restoring p53 levels prevents its degradation. TCTP enhances cell survival though cooperation with Bcl-xl (a protein from the Bcl-2 family) and competition against Bax (pro-apoptotic protein which synthesis is coordinated by p53, the same way as TSAP6). Other regulatory pathways are represented: (1) transcriptional repression of TCTP by p53; (2) transcriptional activation of Siah1b by P53; (3) degradation of NUMB by the Siah1b-E3; and (4) modulation of NUMB though TCTP. Bcl-2, B-cell lymphoma 2; TCTP, translationally controlled tumor protein. Font: The Authors (2021).

Fig. 2

Overview of included studies. Caption: (a) Study setting; (b) Neoplasm submitted to intervention with sertraline; (c) Population according to the approach; (d) Method. AML, acute myeloid leukemia; E, experimental; DMG, diffuse midline glioma; GBM, glioblastoma multiforme; OS, osteosarcoma. Font: The Authors (2021).

Fig. 3

Mapping of mechanisms of action, types of neoplasms and outcomes. Caption: Mapping of mechanisms of action including (a) drug synergism, (b) apoptosis, (c) autophagy; (d) Types of neoplasms submitted to intervention with sertraline; (e) Outcomes of the intervention. AML, acute myeloid leukemia; BTIC, breast tumor initiating cell; Bcl-2, B-cell lymphoma 2; CUSP9, Coordinated Survival Paths Protocol; DTIC, dacarbazine; GBM, glioblastoma multiforme; mTOR/Akt, mammalian target rapamycin/ protein kinase B; OS osteosarcoma; SFA, sphere forming assay; TCTP, translationally controlled tumor protein. Font: The Authors (2021).