ABSTRACT
AIM: This work aimed to determine if the treatment outcomes of bladder cancer could be improved by targeting micelles that are decorated with bladder cancer-specific ligands on the surface and loaded with the chemotherapeutic drug paclitaxel. MATERIALS & METHODS: Targeting efficacy and specificity was determined with cell lines. An in vivo targeting and anti-tumor efficacy study was conducted in mice carrying patient-derived xenografts. RESULTS & DISCUSSION: Targeting micelles were more efficient than nontargeting micelles in delivering the drug load into bladder cancer cells both in vitro and in vivo (p < 0.05). The micelle formulation of paclitaxel was less toxic than free paclitaxel in Cremophor(®) (Sigma, MO, USA) and allowed administration of three-times the maximum tolerated dose without increasing the toxicity. Targeting micelles were more effective than the nontargeting micelles in controlling cancer growth (p = 0.0002) and prolonging overall survival (p = 0.002). CONCLUSION: Targeting micelles loaded with paclitaxel offer strong potential for clinical applications in treating bladder cancer.
Subject(s)
Drug Delivery Systems/adverse effects , Paclitaxel/administration & dosage , Urinary Bladder Neoplasms/drug therapy , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Maximum Tolerated Dose , Mice , Micelles , Paclitaxel/chemistry , Treatment Outcome , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: microRNAs (miRNAs) are endogenous short non-coding RNAs, and play a pivotal role in regulating of a variety of cellular processes, including proliferation and apoptosis, both of which are cellular responses to radiation treatment. The purpose of this study is to identify candidate miRNAs whose levels are altered in response to radiation in prostate cancer cells and to investigate the molecular pathway of such miRNAs in the regulation of radiation-induced cellular response. METHODS: Using a miRNA microarray assay, we screened 132 cancerous miRNAs in LNCaP cells in response to radiation treatment. The function of one candidate miRNA was investigated for checkpoint protein expression, cell cycle arrest, cell proliferation, and cell survival in cells transfected with precursor or antisense miRNA. RESULTS: In response to radiation, multiple miRNAs, including mi-106b, showed altered expression. Cells transfected with precursor miR-106b were able to suppress radiation-induced p21 activation. Functionally, exogenous addition of precursor miR-106b overrode the G2/M arrest in response to radiation and resulted in a transient diminishment of radiation-induced growth inhibition. CONCLUSION: We have shown a novel role of miR-106b, in the setting of radiation treatment, in regulating the p21-activated cell cycle arrest. Our finding that miR-106b is able to override radiation-induced cell cycle arrest and cell growth inhibition points to a potential therapeutic target in certain prostate cancer cells whose radiation resistance is likely due to consistently elevated level of miR-106b.
