ABSTRACT
Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaPR and C4-2BR, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaPR and C4-2BR prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer.
ABSTRACT
Docetaxel-a taxane-based chemotherapeutic agent-was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC.
ABSTRACT
Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid ß-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433-44. ©2018 AACR.
Subject(s)
Bone Neoplasms/metabolism , Bone Neoplasms/secondary , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proteome , Proteomics , Aged , Biomarkers, Tumor , Biopsy , Bone Neoplasms/mortality , Bone Neoplasms/therapy , Combined Modality Therapy , Computational Biology/methods , Gene Expression Profiling , Humans , Male , Middle Aged , Models, Biological , Neoplasm Grading , Prognosis , Prostatic Neoplasms/mortality , Prostatic Neoplasms/therapy , Proteomics/methods , TranscriptomeABSTRACT
Introdução: o Projeto Terapêutico Singular (PTS) é uma abordagem integral à família, que propõe intervenções biopsicossociais, priorizando ações que atenuem os agravos potencializados pelos conflitos intergeracionais. Objetivos: descrever a aplicação de um PTS a uma família com conflitos intergeracionais e morbidades para o estabelecimento de ações depromoção em saúde. Métodos: o trabalho é descritivo, modalidade de relato de caso. O PTS constituiu-se de visita familiar, formulação de hipóteses para intervenção, definição de metas, discussão das metas entre equipe e família e a reavaliação das intervenções planejadas. Nas visitas foi aplicado roteiro semiestruturado contendo o histórico, papeis e relacionamento familiar, agravos, saúde, condições de moradia e higiene, convívio social.Os dados foram compilados nos instrumentos: genograma, ecomapa,escala de risco e diagnóstico multiaxial. Após a concordância da família quanto à divulgação dos dados, os genitores assinaram o Termo de Consentimento Livre e Esclarecido (TCLE). Foi preservado o sigilo dos indivíduos e dos dados coletados. Resultados: por meio da escuta empática e construção de vinculo, a equipe e a família planejaram ações de promoção da saúde e de tratamento de doenças, com enfoque nos agravos: pré-natal de adolescentegravida, planejamento familiar, segmento e adesão ao tratamento dedoenças como hipertensão, hanseníase e erisipela que acometiam indivíduosda família, problemas relacionados ao tabagismo e etilismo; evasão escolar, atualização de vacinas e conflitos intergeracionais. Conclusão: a compreensão do contexto familiar possibilitou o entendimento e a resolução conjuntos do processo saúde-doença e dos agravos potencializados pelo conflito intergeracional.
Introduction: Singular Therapeutic Project (STP) is an integral approachto a family which proposes biopsychosocial interventions andprioritizes actions that mitigate injuries enhanced by intergenerationalconflicts. Objective: describe the application of a STP to a family and its intergenerational conflicts and morbidities to establish health promotionactions. Methods: the article is descriptive in a case reporting format. A STP is consisted of family visits, hypotheses for intervention, goal setting and discussion of goals between family and team and review of planned actions.During visits a semi-structured script with historic, documents, family relationship, injuries, health, living conditions and social interactionhas been applied. Data were compiled in genogram and ecomap, risk scale and multiaxial diagnosis. The family read the document Informed Consent Form (ICF), signed it and agreed whit the publicationof data. Individuals and datas confidentiality have been preserved.Results: through empathic listening, team and family planned togetherhealth promotion actions and diseases treatment, focusing on the injuries:a pregnant teenagers prenatal; family planning; adherence to treatmentof diseases such as hypertension, leprosy and erysipelas, whichhave affected members of the family; and problems related to smokingand alcoholism, high school escape, update immunization and intergenerationconflicts. Conclusion: the comprehension of family context enabled understandingand resolution of health-disease process and injuries potentiated by intergenerational conflicts.
