RESUMEN
Pyrazoles and their derivatives belong to a class of compounds that demonstrate a great potential in design of anticancer, antiangiogenic, and antimetastatic drugs. Our earlier studies showed that pyrazole derivatives TOSPYRQUIN and TOSIND diminished viability of colorectal adenocarcinoma cells HT-29. Here we demonstrated for the first time in human mammary gland adenocarcinoma cell lines MCF7 and MDA-MB-231 cells the cytotoxic effects of four pyrazole derivatives: TOSIND, PYRIND, METPYRIND, and DIPYR. Three pyrazoles: PYRIND, METPYRIND, and one novel unpublished derivative DIPYR were tested for the first time in living cells. Viability of MCF7 did not significantly change in the presence of TOSIND but it decreased after 72 hours of treatment with PYRIND (IC-50 39.7 ± 5.8 µM). In the presence of METPYRIND the viability was also diminished, while DIPYR increased MCF7 viability after 24 hours of incubation. The viability of MDA-MB-231 cells was strongly decreased by TOSIND (IC-50 17.7 ± 2.7 µM 72 h), and was not influenced by PYRIND and METPYRIND, while DIPYR increased the viability and stimulated the growth of MDA-MB-231 cells. PYRIND, METPYRIND and DIPYR caused a gradual decrease of caspase-3 and caspase-7 activities in MDA-MB-231 cells and there was no influence of TOSIND on the activity of both caspases. Our results open the way to search for other compounds with pendant pyrazole residues in order to increase their cytotoxic activity; especially with regard to its anti-breast cancer activity. It appears that the pyrazoles synthesized by us diminish cell viability in a cell-specific manner. This observation might be useful in designing 'off-DNA' anticancer drugs, compounds which are not harmful to the healthy cells.
Asunto(s)
Antineoplásicos/farmacología , Pirazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , HumanosRESUMEN
1. The drugs used in the treatment of rheumatoid arthritis (RA) form a diverse group with unpredictable adverse effects, mostly weak efficacy and variable responses. Despite their differences, a common feature of many anti-inflammatory and disease-modifying anti-rheumatic drugs (DMARD) is inhibition of pro-inflammatory transcription factors, particularly nuclear factor (NF)-kappaB and activator protein (AP)-1. 2. The present brief review identifies those drugs capable of inhibiting transcription factors, particularly steroids, gold salts, D-penicillamine, cyclosporine A and possibly salicylates. 3. The newer biological inhibitors of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta are capable of indirect inhibition of NF-kappaB activation, although even with these potent agents the problem of variability in response has not disappeared. 4. The development of selective inhibitors of the transcription factor NF-kappaB should have the benefit of the anti-inflammatory drugs and DMARD, both new and old. 5. It is hypothesized that this strategy will overcome much of the variability in the therapeutic response and adverse effects that limit the usefulness of the existing drugs in the treatment of RA.