RESUMEN
Considering the high morbidity and mortality rates associated with hematological malignancies and the frequent development of drug resistance by these diseases, the search for new cytotoxic agents is an urgent necessity. The new compounds should present higher efficiency and specificity in inducing tumor cell death, be easily administered and have little or negligible adverse effects. Quinones have been reported in the literature by their several pharmacological properties, including antitumor activity, thus, the aim of this study was to investigate the cytotoxic effect of primin, a natural quinone, on hematological malignancies cell lines. Primin was highly cytotoxic against the three cell lines included in this study (K562, Jurkat and MM.1S) in a concentration- and time-dependent manner, as demonstrated by the MTT method. The compound triggered an apoptotic-like cell death, as observed by ethidium bromide/acridine orange staining, DNA fragmentation and phosphatidylserine exposure after labeling with Annexin V. Both intrinsic and extrinsic apoptosis are involved in cell death induced by primin, as well as the modulation of cell proliferation marker KI-67. The activation of intrinsic apoptosis appears to be related to a decreased Bcl-2 expression and increased Bax expression. While the increase in FasR expression signals activate extrinsic apoptosis. The results suggest that primin is a promising natural molecule that could be used in hematological malignancies therapy or as prototypes for the development of new chemotherapics.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Benzoquinonas/farmacología , Neoplasias Hematológicas/tratamiento farmacológico , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Factor Inductor de la Apoptosis/metabolismo , Benzoquinonas/efectos adversos , Benzoquinonas/aislamiento & purificación , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Eugenia/química , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Células Jurkat , Células K562 , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Acute leukemias are a heterogeneous group of aggressive malignant neoplasms associated with severe morbidities due to the nonselectivity of current chemotherapeutic drugs to nonmalignant cells. The investigation of novel natural and synthetic structures that might be used for the development of new drugs with greater efficiency and selectivity to leukemic cells is mandatory. In this context, thiosemicarbazones have been well described in the literature by their several biological properties and their reaction is known as versatile, low-cost, and highly chemoselective. With this perspective, this study aimed to investigate the cytotoxic effect and the main death mechanisms of a novel thiosemicarbazone (LAP17) on acute leukemia cell lines K562 and Jurkat. The results show that the strong cytotoxic effect of LAP17 to leukemic cells is due to apoptosis induction, which resulted in caspase-3 activation and DNA fragmentation. Intrinsic apoptosis seems to be related to the inversion of Bax/Bcl-2 expression, ΔΨm loss, and AIF release, whereas extrinsic apoptosis was initiated by FasR. Gene-expression profiling of HL-60 cells treated with LAP17 by the microarray technique revealed a significant enrichment of gene sets related to cell cycle arrest at G2/M. Accordingly, K562 and Jurkat cells treated with LAP17 revealed a clear arrest at G2/M phase. Taking into consideration that LAP17 was not cytotoxic to nonhematological cells (peripheral blood mononuclear cell and erythrocytes), these results suggest that LAP17 is a promising new compound that might be used as a prototype for the development of new antileukemic agents.
Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tiosemicarbazonas/química , Antineoplásicos/química , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ciclo Celular , Proliferación Celular , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Potencial de la Membrana Mitocondrial , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células Tumorales CultivadasRESUMEN
Aim: Investigate the apoptotic mechanisms of two new aldehyde biphenyl chalcones on leukemia cells. Materials & methods: From a series of 71 new chalcones, we selected the two most cytotoxic. Results: JA3 and JA7 were cytotoxic not only against hematological malignancies but also against solid tumor and cancer stem cells, yet with no toxicity to normal cells. Moreover, they induced immunogenic apoptotic-like cell death independently of promyelocytic leukemia protein, with extensive mitochondrial damages downstream of endoplasmic reticulum stress. Preventing endoplasmic reticulum stress and the upregulation of proapoptotic machinery inhibited JA3- and JA7-induced cell death. Likewise, blocking receptor Fas protected cells from killing. They increased the antileukemic effect of cytarabine and vincristine and killed leukemic cells collected from patients with different acute leukemia subtypes. Conclusion:JA3 and JA7 represent new promising prototypes for the development of new chemotherapeutics.