Estudios científicos
Cytotoxic and biochemical effects of 3,3',4,4',5,5'-hexahydroxystilbene, a novel resveratrol analog in HL-60 human promyelocytic leukemia cells
Abstract:
OBJECTIVE: Resveratrol (3,4',5,-trihydroxystilbene, RV), an ingredient of wine, is an inhibitor of the proliferation-linked enzyme ribonucleotide reductase (RR) and shows a broad spectrum of cytotoxic effects against human cancer cells. In order to enhance these effects, we introduced additional hydroxyl moieties into the molecule. In the present study, the activity of a novel RV analog, 3,3',4,4',5,5'-hexahydroxystilbene (M8), was investigated in HL-60 human promyelocytic leukemia cells.
METHODS: Cytotoxicity of M8 alone or in combination with Ara-C was assessed employing growth inhibition assays. Effects of M8 on nucleoside triphosphates (NTPs) and deoxynucleoside triphosphates (dNTPs) were examined by HPLC. The apoptotic potential of M8 and RV was compared using a specific double-staining method and inhibition of TNF-alpha-induced activation of NF-kappaB was studied. Cell-cycle distribution was analyzed by FACS.
RESULTS: Addition of ascorbic acid decreased the IC(50) value of M8 from 6.25 microM to 2 microM. M8 depleted dATP and dTTP pools to 41% and 21% of control values, whereas dCTP pools increased to 199% of untreated controls. In addition, TTP, ATP, CTP, and GTP concentrations were decreased while UTP concentrations increased. M8 induced apoptosis at concentrations significantly lower than RV and could remarkably inhibit the activation of NF-kappaB. M8 arrested cells in the S phase of the cell cycle while depleting cells in the G2-M phase and exhibited synergistic combination effects when applied simultaneously with Ara-C.
CONCLUSION: Due to these promising results, this novel polyhydroxylated stilbene derivative might become an additional option for the treatment of leukemia and therefore deserves further preclinical and in vivo testing.
Comentarios divulgativos:
El resveratrol un ingrediente del vino es un inhibidor de la ribonucleótido reductasa (RR) y muestra un amplio espectro de efectos citotóxicos contra las células de cáncer humano. Con el fin de mejorar estos efectos, se introdujeron más restos hidroxilo en la molécula. En el presente estudio, la actividad de un análogo del RV 3,3 ', 4,4', 5,5 '-hexahydroxystilbene (M8), se ha investigado en células HL-60 humanas de leucemia promielocítica.
La adición de ácido ascórbico disminuyó la IC (50) El valor de M8 de 6,25 a 2 microM microM. M8 empobrecido dATP y el pool de dTTP al 41% y 21% de los valores control, mientras que el pool de dCTP es mayor en un 199% que en los controles no tratados. Además, las concentraciones TTP, el ATP, CTP y GTP se redujeron mientras que las concentraciones UTP aumentaron.
Debido a estos resultados prometedores, esta nueva podría convertirse en una opción adicional para el tratamiento de la leucemia y por lo tanto merece más ensayos preclínicos y en ensayos in vivo.
