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

Abstract:
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 concentrations of 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
of microtubules.