RESUMEN
Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved. The results indicate that piperine induced CS, being more cytotoxic to K562-derived MDR cells (Lucena-1 and FEPS) than to K562, the parental CML cell. CS was confirmed by analysis of cell metabolic activity and viability, cell morphology and apoptosis. P-gp was partially required for CS induction. To investigate a P-gp independent mechanism, we analyzed the possibility that poly (ADP-ribose) polymerase-1 (PARP-1) could be involved in piperine cytotoxic effects. It was previously shown that only MDR FEPS cells present a high level of 24 kDa fragment of PARP-1, which could protect these cells against cell death. In the present study, piperine was able to decrease the 24 kDa fragment of PARP-1 in MDR FEPS cells. We conclude that piperine targets selectively MDR cells, inducing CS, through a mechanism that might be dependent or not on P-gp.
Asunto(s)
Alcaloides/farmacología , Apoptosis , Benzodioxoles/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Supervivencia Celular , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismoRESUMEN
Resumen En el siglo XXI, la humanidad se encuentra frente a una era post-antibiótica, en la cual es común la aparición de infecciones con una menor o nula alternativa terapéutica. En este contexto, se hace indispensable implementar medidas que optimicen el arsenal terapéutico disponible, generando nuevas estrategias para contrarrestar la creciente resistencia bacteriana y la era post-antibiótica. Las interacciones evolutivas plantean que el desarrollo de susceptibilidad o resistencia de un microorganismo a un antimicrobiano tendrá un efecto inverso (susceptibilidad colateral) o similar (resistencia cruzada) en un segundo antimicrobiano incorporado en este sistema. Las interacciones evolutivas se plantean como un nuevo mecanismo de interacción medicamentosa, al tiempo que se identifica a la susceptibilidad colateral como una estrategia terapéutica para combatir la resistencia bacteriana, que se podría integrar y evaluar en un futuro como una nueva estrategia en los programas de gerenciamiento de antimicrobianos.
In the 21st century, the world is facing a post-antibiotic era, in which the appearance of infections with a minor or no therapeutic alternative is common. In this context, it is essential to implement measures that optimize the available therapeutic tool, thus generating new strategies that strengthen the fight against growing bacterial resistance. The evolutionary interactions suggest that the development of sensitivity or resistance of a microorganism to an antimicrobial will have an inverse effect (collateral sensitivity) or similar (cross resistance) in a second antimicrobial that is involved in this system. The evolutionary interactions are considered as a new mechanism of drug interaction, and additional, it establishes the collateral sensitivity as a therapeutic strategy to combat bacterial resistance, which could be integrated and evaluated in the future as a new strategy in the antimicrobial stewardship programs.