RESUMO
Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway plays a key role in the tumorigenesis of a variety of human cancers including ovarian cancer. However, inhibitors of this pathway such as Rad001 have not shown therapeutic efficacy as a single agent for this cancer. Arsenic trioxide (ATO) induces an autophagic pathway in ovarian carcinoma cells. We found that ATO can synergize with Rad001 to induce cytotoxicity of ovarian cancer cells. Moreover, we identified synergistic induction of autophagy and apoptosis as the likely underlying mechanism that is responsible for the enhanced cytotoxicity. The enhanced cytotoxicity is accompanied by decreased p-AKT levels as well as upregulation of ATG5-ATG12 conjugate and LC3-2, hallmarks of autophagy. Rad001 and ATO can also synergistically inhibit tumors in a xenograft animal model of ovarian cancer. These results thus identify and validate a novel mechanism to enhance and expand the existing targeted therapeutic agent to treat human ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/administração & dosagem , Autofagia/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Everolimo , Feminino , Humanos , Imunossupressores/administração & dosagem , Camundongos , Camundongos SCID , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Óxidos/administração & dosagem , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PI3K/AKT/mTOR pathway plays a key role in the tumorigenesis of many human cancers including prostate cancer. However, inhibitors of this pathway, such as Rad001, have not shown therapeutic efficacy as a single agent. Through a high-throughput screen of 5,000 widely used small molecules, we identified compounds that can synergize with Rad001 to inhibit prostate cancer cells. One of the compounds, propachlor, synergizes with Rad001 to induce apoptosis of castration-resistant prostate cancer cells via enhanced autophagy. This enhanced autophagic cell death is accompanied by increased Beclin1 expression as well as upregulation of Atg5-Atg12 conjugate and LC3-2. Rad001 and propachlor can also synergistically inhibit tumors in a xenograft animal model of prostate cancer. These findings provide a novel direction to develop combination therapies for advanced and metastatic prostate cancer that has failed the currently available therapies.
