RESUMO
Despite many advances in oncology, almost all patients with pancreatic cancer (PC) die of the disease. Molecularly targeted agents are offering hope for their potential role in helping translate the improved activity of combination chemotherapy into improved survival. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes such as cancer. Further, Hsp27 expression becomes highly upregulated in cancer cells after chemotherapy. Recently, a modified antisense oligonucleotide that is complementary to Hsp27 (OGX-427) has been developed, which inhibits Hsp27 expression and enhances drug efficacy in cancer xenograft models. Phase II clinical trials using OGX-427 in different cancers like breast, ovarian, bladder, prostate and lung are in progress in the United States and Canada. In this study, we demonstrate using TMA of 181 patients that Hsp27 expression and phosphorylation levels increase in moderately differentiated tumors to become uniformly highly expressed in metastatic samples. Using MiaPaCa-2 cells grown both in vitro and xenografted in mice, we demonstrate that OGX-427 inhibits proliferation, induces apoptosis and also enhances gemcitabine chemosensitivity via a mechanism involving the eukaryotic translation initiation factor 4E. Collectively, these findings suggest that the combination of Hsp27 knockdown with OGX-427 and chemotherapeutic agents such as gemcitabine can be a novel strategy to inhibit the progression of pancreas cancer.
Assuntos
Desoxicitidina/análogos & derivados , Proteínas de Choque Térmico HSP27/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Neoplasias Pancreáticas/terapia , Animais , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Progressão da Doença , Sinergismo Farmacológico , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Masculino , Camundongos , Camundongos Nus , Chaperonas Moleculares , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
Castration-resistant prostate cancer remains incurable and a major cause of mortality worldwide. The absence of effective therapeutic approaches for advanced prostate cancer has led to an intensive search for novel treatments. Emerging nanomedical approaches have shown promising results, in vitro and in vivo, in improving drug distribution and bioavailability, tumor penetration and in limiting toxicity. Nanoscaled carriers bearing finely controlled size and surface properties such as liposomes, dendrimers and nanoparticles have been developed for successful passive and active tumortargeting. Enhanced pharmacokinetics of nanotherapeutics, through improved target delivery and prolonged tissue halflife provides optimal drug delivery that is tumor-specific. Tumor-targeting may be improved through ligand directed delivery systems binding to tumor-specific surface receptors improving cellular uptake through receptor-mediated endocytosis. Recently published data have provided pre-clinical evidence showing the potential of active-targeted nanotherapeutics in prostate cancer therapy; unfortunately, only a few of these therapies have translated into early phase clinical trials development. Hence, progress of active-targeted nanotherapy improving efficiency of site-specific drug delivery is a critical challenge in future clinical treatment of prostate cancer. Exploring specific prostate cell-surface antigens or receptor overexpression may elaborate promising strategies for future therapeutic design. This review presents an overview of some new strategies for prostate cancer active-targeting nanotherapeutics.
