RESUMO
Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Proteínas rho de Ligação ao GTP/genética , Autofagia/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Female heroin addict clients suffer neglect of various kinds in connection with research efforts dealing with addiction. Often they are omitted altogether. Or, if included, topics relevant to their lives are not always examined, or a double standard of evaluation or interpretation, which operates to their disadvantage, is sometimes utilized. The study reported here was undertaken as a partial remedy for these ills. Its primary aim was to characterize a group of female heroin addicts at the time that they entered a city-run treatment program. Males were studied as well, however, so as to permit an examination of sex differences which might suggest modifications in male-oriented treatment programs.
Assuntos
Serviços de Saúde Comunitária , Dependência de Heroína/terapia , Adulto , Pessoal Técnico de Saúde , Conscientização , Anticoncepção , Psicologia Criminal , District of Columbia , Etnicidade , Características da Família , Feminino , Humanos , Masculino , Relações Pais-Filho , Paridade , Gravidez , Assistência Pública , Fatores Sexuais , Comportamento Sexual , Meio Social , Fatores de Tempo , DesempregoRESUMO
The majority of both male and female heroin addicts entering a city treatment program were introduced to heroin by a male. But by contrast with the males, females were in many cases introduced to heroin by another woman, more often used drugs with persons of both sexes, and were more likely to be living with a current or former heroin user at intake. Encouragement to give up drugs was reported more frequently by both men and women than attempts to discourage their entry into treatment, but only the encouragement of the spouse or opposite-sexed partner was significantly related to treatment outcome.