The ester derivatives obtained by C-ring modification of podophyllotoxin induce apoptosis and inhibited proliferation in PC-3M cells via down-regulation of PI3K/Akt signaling pathway

Abstract

Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially its anti-tumor effects. To improve the cytotoxicity and selective effect of PPT, in this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of PPT. The cytotoxicity of these compounds was evaluated with PC-3M, HemECs, A549, MCF-7 and HepG2 cells. We observed that the proliferation of PC-3M cells was inhibited by all 20 ester derivatives in the largest degree, comparing to the other cell lines. Comparing to PPT (IC50 = 234.90 ± 20.7 nM), eight derivatives had better performance in inhabiting proliferation of PC-3M cells, six of them belong to Boc-amino acid ester derivatives, and the derivative named V-05 (IC50 = 1.28 ± 0.1 nM) had the strongest inhibitation effect. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, flow cytometry and western blot analysis. We found that V-05 were able to inhibit PC-3M cells proliferation and migration, and induced apoptosis by downregualting p-PI3K, p-Akt and Bcl-2, and upregulating Cleaved caspase-3 and Bax. Our research provides the first insight for the application of PPT derivatives in PC-3M cells, which may offer information to the effective medicine development for human prostate cancer treatment.