Blocking Autophagy by the Two-Pore Channels Antagonist Tetrandrine Improves Sorafenib-Induced Death of Hepatocellular Carcinoma Cells

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Sperandio, Leticia Paulino ; Lins, Isis Valeska F. ; Erustes, Adolfo G. ; Leao, Anderson H. F. F. ; Antunes, Fernanda ; Morais, Ingrid B. M. ; Vieira, Heron Fernandes ; de Campos, Lais Maria ; Bincoletto, Claudia ; Smaili, Soraya S. ; Pereira, Gustavo J. S.

• Document type: Journal article
• Source: TOXICOLOGY IN VITRO; v. 90, p. 11-pg., 2023-05-12.

Abstract

Sorafenib, an oral multi-kinase inhibitor, used to treat hepatocellular carcinoma (HCC). However, drug resistance is still common in several HCC patients. This complex mechanism is not yet fully elucidated, driving the search for new therapeutic targets to potentiate the antitumoral effect of sorafenib. Recent findings have linked the expression of Two-Pore Channels (TPCs) receptors with the development and progression of cancer. TPCs receptors are stimulated by NAADP, a Ca2+ messenger, and inhibited by their antagonists Ned-19 and tetrandrine. Here, we investigate the participation of TPCs inhibition in cell death and autophagy in sorafenib-treated HCC cells. Here, we show that the association of sorafenib with tetrandrine increased sorafenib-induced cell death accompanied by increased lysotracker fluorescence intensity. In contrast, these effects were not observed after treating these cells with Ned-19. The pharmacological TPC antagonists by Ned-19 and tetrandrine or siRNAmediated TPC1/2 inhibition decreased sorafenib-induced Ca2+ release, reinforcing the participation of TPCs in sorafenib HCC responses. Furthermore, the association tetrandrine and sorafenib blocked autophagy through ERK1/2 pathway inhibition, which represents a putative target for potentiating HCC cell death. Therefore, our study proposes the use of tetrandrine analogs with the aim of improving sorafenib therapy. Also, our data also allow us to suggest that TPCs may be a new target in anticancer therapies. (AU)

• FAPESP's process: 19/14722-4 - Two-Pore Channels receptors and TFEB-3 autophagy modulation in human hepatocellular carcinoma
• Grantee: Gustavo José da Silva Pereira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/10863-7 - Study of lipophagy mediated by two-pore channels receptors
• Grantee: Gustavo José da Silva Pereira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/02821-8 - Autophagy modulation by cannabinoids: neuroprotection in Parkinson's Disease
• Grantee: Soraya Soubhi Smaili
• Support Opportunities: Research Projects - Thematic Grants