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 drug-resistant 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.
Department of Integrated Oncological Therapies, IRCCS AOU S. Martino-IST, Genoa, Italy. maurizio.viale@istge.it
Maurizio
M
Viale
Maria
M
Anzaldi
Cinzia
C
Aiello
Carla
C
Fenoglio
Federica
F
Albicini
Laura
L
Emionite
Rosaria
R
Gangemi
Alessandro
A
Balbi
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D026901:Membrane Transport Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C031280:pyrazole; C421109:multidrug resistance-associated protein 1