Open AccessCompound A398, a Novel Podophyllotoxin Analogue: Cytotoxicity and Induction of Apoptosis in Human Leukemia Cells
Author(s) -
Alethéia Lacerda da Silveira,
Gláucia V. Faheina–Martins,
Raquel Ciuvalschi Maia,
Demétrius Antônio Machado de Araújo
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0107404
Subject(s) - apoptosis , podophyllotoxin , cytotoxicity , programmed cell death , dna fragmentation , caspase , p38 mitogen activated protein kinases , kinase , phosphatidylserine , biology , dna damage , reactive oxygen species , microbiology and biotechnology , cytotoxic t cell , cell culture , cancer cell , depolarization , cancer research , chemistry , biochemistry , mapk/erk pathway , cancer , dna , in vitro , stereochemistry , biophysics , genetics , phospholipid , membrane
Despite advances in oncology research, cancer is one of the leading causes of death worldwide. Thus, there is a demand for the development of more selective and effective antitumor agents. This study showed that A398, a novel podophyllotoxin analogue, was cytotoxic to the HT-29, MCF-7, MOLT-4 and HL-60 tumor cell lines, being less active in human peripheral blood mononuclear cells and normal cell lines FGH and IEC-6. Tests using the HepG2 lineage indicated that its metabolites do not contribute to its cytotoxicity. In the HL-60 cells, A398 induced apoptosis in a time and concentration-dependent manner, promoting mitochondrial depolarization, inhibition of Bcl-2, phosphatidylserine exposure, activation of caspases -8, -9 and -3, and DNA fragmentation. The production of reactive oxygen species does not seem to be a crucial event for the apoptotic process. Pretreatment with specific inhibitors of kinases ERK1/2, JNK and p38 resulted in an increased percentage of death induced by A398. These results indicate that the compound induced apoptosis through activation of intrinsic and extrinsic death pathways with the mechanism involving the inhibition of the MAPKs and Bcl-2. Taken together, our findings suggest that A398 has an anticancer potential, proving itself to be a candidate for preclinical studies.