Compound A398, a Novel Podophyllotoxin Analogue: Cytotoxicity and Induction of Apoptosis in Human Leukemia Cells

Abstract

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.

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“…The mechanism involves the inhibition of MAPKs and Bcl-2 to induce apoptosis through the activation of intrinsic and extrinsic death pathways. 114 GL-331 is a semisynthetic TOP2 inhibitor that is less cytotoxic than etoposide. GL-331 induces apoptotic cell death through the activation of protein tyrosine phosphatases.…”

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“…48 h later, the medium was changed to DMEM without any stimuli, supplemented with only 1% P/S. Cell viability was measured at this time point and one and five days after removing the stimuli as described in our previous studies [ 39 , 40 ]. In brief, 100 µL MTT solution was added to hPDLSCs followed by two hours incubation at 37 °C.…”

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“…GMZ-1 suppresses growth and induces apoptosis in adriamycinresistant K562/A02 cells through modulation of MDR1 expression [269]. A398was cytotoxic to the HT-29, MCF-7, MOLT-4 and HL-60 tumor cell lines [270].…”