RESUMEN
Volasertib (BI 6727), a highly selective and potent inhibitor of PLK1, has shown broad antitumor activities in the preclinical and clinical studies for the treatment of several types of cancers. However, the anticancer effect of volasertib on cervical cancer cells is still unknown. In the present study, we show that volasertib can markedly induce cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the decreased protein expressions of PLK1 substrates survivin and wee1 in human cervical cancer cells. Furthermore, volasertib also enhances the intracellular reactive oxidative species (ROS) levels, and pretreated with ROS scavenger N-acety-L-cysteine totally blocks ROS generation but partly reverses volasertib-induced apoptosis. In addition, volasertib significantly potentiates the activity of cisplatin to inhibit the growth of cervical cancer in vitro and in vivo. In brief, volasertib suppresses tumor growth and potentiates the activity of cisplatin in cervical cancer, suggesting the combination of volasertib and cisplatin may be a promising strategy for the treatment of patients with cervical cancer.
RESUMEN
Ovarian cancer is one of the most lethal of woman cancers, and its clinical therapeutic outcome currently is unsatisfied. Dinaciclib, a novel small molecule inhibitor of CDK1, CDK2, CDK5 and CDK9, is assessed in clinical trials for the treatment of several types of cancers. In this study, we investigated the anticancer effects and mechanisms of dinaciclib alone or combined with cisplatin in ovarian cancer. Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin. Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib. Moreover, the combination of dinaciclib with cisplatin synergistically promoted cell cycle arrest and apoptosis, and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cisplatino/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Piridinio/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Óxidos N-Cíclicos , Quinasas Ciclina-Dependientes/metabolismo , Sinergismo Farmacológico , Femenino , Células HEK293 , Humanos , Indolizinas , Concentración 50 Inhibidora , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Compuestos de Piridinio/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer.