Evaluation of the anti-proliferative activity of three new pyrazole compounds in sensitive and resistant tumor cell lines

Background: in previous papers we demonstrated that the activity of short heteroretinoids as anti-proliferative and pro-apoptotic compounds was deeply linked to their heterocyclic moiety and that ionone-derived 1,5-pyrazoles had the highest anti-proliferative activity in our preliminary experiments. we then demonstrated the high and pharmacologically significant anti-proliferative and apoptotic activities of the pyrazole compounds 2-(1-(4-chlorophenyl)-1h-pyrazol- 5-yl)-5-methoxyphenol (en12-4),5-methoxy- 2-(1-(pyridin-2-yl)-1h-pyrazol-5-yl) phenol (en12-2a) and 2-(5-(4-methoxyphenyl)-1h-pyrazol-1-yl)pyridine (en7-2) establishing,especially for en12-2a,a possible mechanism of action involving the cell microtubular system. methods: here,the anti-proliferative activity of these pyrazole compounds was analyzed in vitro by the mtt assay in six drugresistant cell lines,five of which were selected after exposure to increasing concentrationsof cisplatin (l1210/ddp),doxorubicin (a2780/dx3),5-fluorouracil (hct-8/5fu),taxol (a549/t24) and etoposide (mcf-7/vp),and one was obtained by transfection of the abcg2 membrane transporter (hek-293/r2). results: our data show that these compounds have a similar anti-proliferative activity in nearly all resistant and sensitive cell lines,demonstrating their ability to overcome the most common mechanisms of drug resistance with two exceptions regarding the mcf-7/vp cell line over-expressing the abcc1 (mrp1) transporter,and the mdr1 over-expressing a2780/dx3 cells,with a calculated ri = 3.2 for en12-2a,relative to their sensitive cellular counterpart. on the other hand,the taxol-resistant a549/t24 cell line showed a significantly increased sensitivity to our compounds. conclusions: our data suggest that our pyrazole compounds are able to overcome in vitro the most common drug-resistance mechanisms demonstrating a significant anti-proliferative activity and confirming a mechanism of action involving the depolymerization ofmicrotubules. copyright © 2013 by institute of pharmacology polish academy of sciences.