Avaliação do potencial antitumoral de derivados do AAL-993 em modelos representativos de carcinoma hepatocelular

Abstract

Liver cancer represents the second leading cause of cancer-related death in males, and it is estimated that approximately one million deaths will occur by 2030 due to this type of cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and, in general, it is diagnosed in an advanced stage. The therapies are few effective and the therapeutic arsenal is very limited. Sorafenib (Nexavar®), a multikinase inhibitor, has been used since 2007 as the first-line drug for the treatment of advanced-stage HCC. In 2018, the lenvatinib was also approved for HCC treatment, however with modest therapeutic efficiency. In this scenario, there is a constant search for new substances potentially active against HCC. The present study aimed to evaluate the effects of N-acylhydrazone derivatives (LASSBio-2027, LASSBio-2029 e LASSBio-2052) obtained from ALL-993 chemical scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2), on proliferative behavior of HepG2 and Hep3B cells, which have been widely used as study model for HCC. The results showed that all evaluated derivatives were effective in reducing cell viability in HepG2 and Hep3B cultures in a dose-dependent manner. Based on IC50 values, the cytotoxic activity of LASSBio-2052 was more prominent than LASSBio-2027 and LASSBio-2029. It was demonstrated that LASSBio-2052 inhibits the proliferation of HepG2 and Hep3B cells by modulating the expression of regulators of G2/M transition. There was a reduction in mRNA abundance for genes that encode important kinase proteins for mitosis entering, including AURKA (Aurora A), AURKB (Aurora B), PLK1, and CDK1. The relative expression of FOXM1 was also reduced in response to treatment, which compromises the transcriptional activation of genes required for G2/M transition. The antiproliferative activity of LASSBio-2052 was reinforced by significant reduction in cyclin D and cyclin B at protein levels, and pERK downregulation. Taken together, the data indicate that has promising antitumor activity, however, additional studies should be performed to identify the molecular target underlying its ability to suppress concomitantly the expression of regulatory genes of G2/M transition.