RESUMEN
The mevalonate pathway plays an important role in cancer biology and has been targeted with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. Statins and bisphosphonates inhibit the mevalonate pathway at different steps, thus having negative effects at various levels on cancer cells. A combination of these drugs may result in an amplified cytotoxic effect and allow for use of significantly lower doses of the drugs involved. Statins inhibit the mevalonate pathway at 3-hydroxy-3-methylglutaryl coenzyme A reductase and bisphosphonates at farnesyl pyrophosphate synthase. Our results show that low-dose combinations of simvastatin and alendronate have a synergistic cytotoxic effect on androgen-independent prostate cancer PC-3 cells, but not on androgen-dependent LNCaP or DU 145 prostate cancer cells. These two drugs cause a sequential blockade of the mevalonate pathway and significantly affect survival and apoptotic pathways by down-regulating phospho-AKT and activating c-JUN and ERK.
Asunto(s)
Alendronato/administración & dosificación , Sinergismo Farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Simvastatina/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/biosíntesis , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/biosíntesisRESUMEN
Topoisomerase 1 inhibitors cure human cancer xenografts in animal models, more so than most other chemotherapy agents. However, their activity in patients with cancer is modest. Ongoing research is studying the optimal analogues that could reproduce animal data in the cancer population. This article analyzes the clinical research with topoisomerase 1 inhibitors in ovarian cancer.