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Apoptosis oxidative damage‐mediated and antiproliferative effect of selenylated imidazo[1,2‐ a ]pyridines on hepatocellular carcinoma HepG2 cells and in vivo
Author(s) -
Santos Daniela Coelho,
Rafique Jamal,
Saba Sumbal,
Almeida Gabriela M.,
Siminski Tâmila,
Pádua Cynthia,
Filho Danilo W.,
Zamoner Ariane,
Braga Antonio L.,
Pedrosa Rozangela C.,
Ourique Fabiana
Publication year - 2021
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.22663
Subject(s) - apoptosis , chemistry , in vivo , cell growth , cancer research , kinase , dna fragmentation , cell cycle , angiogenesis , pharmacology , cytotoxicity , programmed cell death , biochemistry , in vitro , biology , microbiology and biotechnology
Imidazo[1,2‐ a ]pyridines (IP) and organoselenium compounds have been widely exploited in medicinal chemistry due to their pharmacological activities. Hepatocellular carcinoma (HCC) has few treatment options, and unfortunately, the prognosis is poor. Thus, the development of novel therapeutic drugs is urgent. The present study aimed at evaluating the antitumor mechanism of selenylated IP against HepG2 cells and in vivo. The selenylated IP named IP‐Se‐06 (3‐((2‐methoxyphenyl)selanyl)‐7‐methyl‐2‐phenylimidazol[1,2‐ a ]pyridine) showed high cytotoxicity against HepG2 cells (half‐maximal inhibitory concentration [IC 50 ] = 0.03 µM) and selectivity for this tumor cell line. At nontoxic concentration, IP‐Se‐06 decreased the protein levels of Bcl‐xL and increased the levels of p53, leading to inhibition of cell proliferation and apoptosis. This compound decreased the level of extracellular signal‐regulated kinase 1/2 protein and changed the levels of proteins involved in the drive of the cell cycle, tumor growth, and survival (cyclin B1, cyclin‐dependent kinase 2). In addition, IP‐Se‐06 decreased the number of cells in the S phase. In addition, IP‐Se‐06 led to increased generation of reactive oxygen species, changed antioxidant defenses, and caused DNA fragmentation. Finally, IP‐Se‐06 significantly inhibited the growth of Ehrlich ascites tumors in mice, increased survival time, and inhibited angiogenesis. Therefore, IP‐Se‐06 may be an important compound regarding the development of a therapeutic drug for HCC treatment.