Diallyl Disulfide Induces Chemosensitization to Sorafenib, Autophagy, and Cell Cycle Arrest and Inhibits Invasion in Hepatocellular Carcinoma

Author(s)

Machado, Ana Rita Thomazela ; Tuttis, Katiuska ; Santos, Patrick Wellington da Silva ; Aissa, Alexandre Ferro ; Antunes, Lusania Maria Greggi

• Document type: Journal article
• Source: PHARMACEUTICS; v. 14, n. 12, p. 18-pg., 2022-12-01.

Abstract

Hepatocellular carcinoma is the seventh most common type of cancer in the world, with limited treatment options. A promising strategy to treat cancer is to associate chemotherapeutics and plant bioactive compounds. Here, we examined whether diallyl disulfide (DADS; 50-200 mu M) and sorafenib (SORA; 8 mu M), either alone or in combination, were toxic to hepatocellular carcinoma cells (HepG2) in vitro. We assessed whether DADS and/or SORA induced cell death (LIVE/DEAD assay and autophagy) and cell cycle changes (flow cytometry), altered expression of key genes and proteins (RT-qPCR and Western blot), and modulated tumorigenesis signatures, such as proliferation (clonogenic assay), migration (wound healing), and invasion (inserts). The DADS + SORA combination elicited autophagic cell death by upregulating LC3 and NRF2 expression and downregulating FOS and TNF expression; induced the accumulation of cells in the G1 phase which thereby upregulated the CHEK2 expression; and inhibited invasion by downregulating the MMP2 expression. Predictive analysis indicated the participation of the MAPK pathway in the reported results. The DADS + SORA combination suppressed both cell invasion and clonogenic survival, which indicated that it dampened tumor growth, proliferation, invasion, and metastatic potential. Therefore, the DADS + SORA combination is a promising therapy to develop new clinical protocols. (AU)

• FAPESP's process: 19/08348-2 - Toxicological evaluation of diallyl disulfide associated with the chemotherapeutic agent sorafenib: investigation of cell death and expression of proteins in human liver cells in vitro
• Grantee: Ana Rita Thomazela Machado
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/24576-0 - Effects of nutraceuticals sulforaphane, diallyl disulfide and vitamin D in human cancer cell lines: Evaluation of cytotoxicity, genotoxicity, cell migration, epigenetics changes and gene expression
• Grantee: Lusânia Maria Greggi Antunes
• Support Opportunities: Regular Research Grants