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Abstract
Multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer
treatment. To overcome MDR, a serious of pyridine acid esters of podophyllotoxin was
synthesized and their antiproliferation activities were evaluated against two human
chronic myeloid leukemia cell lines in vitro. Most of them exhibited potent growth
inhibition with IC50 values in the nanomolar range as well as markedly reduced resistance
factors. The most potent compound, Y8 exhibited an IC50 of 0.046±0.003μM against resistance
K562/ADR cells, showing more significant than that of adriamycin and etoposide, respectively.
Furthermore, Y8 efficiently triggered cell cycle arrest at S phase and simultaneously
induced apoptosis in K562/ADR cells. Meanwhile, Y8 also regulated the expression levels
of cell cycle- and apoptosis-related proteins. Additionally, Y8 stimulated the ERK1/2
signalling and reduced the expression of Pgp protein. Finally, on the basis of results
obtained using U0126, an ERK1/2 inhibitor, the ERK1/2 signalling pathway was proposed
for the multidrug resistance-reversing effect of Y8 in K562/ADR cells. Together, Y8
could be a novel potential MDR reversal agent for the treatment of drug-resistant
leukemia.