Abstract. Miconazole (MIC), an antifungal agent, diplays anti-tumorigenic activity in various types of human cancers, including bladder cancer, yet its mechanism of antitumor action is not well understood. In the present study, we demonstrated that, in a cell viability assay, MIC had a cytotoxic effect on human T24, J82 and TSGH-8301 bladder cancer cells in a dose-and time-dependent manner, but did not exhibit significant toxicity toward human peripheral blood mononuclear cells. Cell cycle analysis revealed that MIC at concentrations of 25 and 50 µM significantly caused G0/G1 arrest in the TSGH-8301 and T24 cells, respectively. DNA fragmentation, mitochondrial membrane potential and western blot analyses showed that MIC inhibited the growth of these cells by both mitochondrial-mediated and death receptor (DR5)-mediated apoptosis pathways. Specifically, MIC increased the protein levels of p21 and p27, but decreased the expression of cyclin E1, CDK2 and CDK4. MIC augmented the expression of DR5, cleaved forms of caspase-3 -8 and -9, poly(ADP-ribose) polymerase and Bax, decreased the expression of Bcl-2 but increased cytosol levels of cytochrome c. Our results suggest that MIC inhibits the growth of bladder cancer cells through induction of G0/G1 arrest and apoptosis via activation of both the extrinsic and intrinsic apoptotic pathways. MIC is a potential chemotherapeutic agent for treating bladder cancer in humans.
Escin, a natural pentacyclic triterpenoid compound, exhibits antitumor effects on various types of human cancer cells, but its effect on human renal cancer cells has not been fully elucidated. In the present study, we demonstrated that escin elicits cytotoxic effects on human renal cancer cells (786-O and Caki-1) in a dose-dependent manner, as determined by MTT assay. Escin induced G2/M arrest, and then increased the sub-G1 population, Annexin V binding, activation of caspase-9/-3, cleavage of poly(ADP-ribose) polymerase (PARP) and Bax protein. Escin also decreased the anti-apoptotic protein levels of Bcl-2, X-linked inhibitor of apoptosis protein and survivin. In addition, escin induced reactive oxygen species (ROS) generation, leading to mitochondrial membrane potential dysfunction and inducing apoptosis in 786-O renal cancer cells, which were suppressed by antioxidants, such as NAC. Collectively, our results suggest that escin induces apoptosis via the intrinsic-mitochondrial apoptosis pathway through G2/M arrest and ROS generation in human renal cancer cells. Escin appears to have potential as a clinically useful chemotherapeutic agent for human renal cancer.
Purpose: To investigate the prognostic efficacy of the Geriatric Nutritional Risk Index (GNRI) in patients with metastatic Castration–resistant Prostate Cancer (mCRPC) receiving docetaxel as the first line of treatment.Methods: We retrospectively reviewed patients with mCRPC and receiving first line docetaxel in Taichung Veterans General Hospital from 2006 to 2012. The GNRI was calculated using serum albumin and body mass index, with a poor nutritional status defined as GNRI <92.0. Multivariate Cox-regression analysis was used to evaluate the risk of survival.Results: One-hundred seventy patients with mCRPC were included. One-hundred twenty-five patients were of normal nutritional status (GNRI ≥92) and 45 patients were of poor nutritional status (GNRI <92). The cumulative docetaxel dosage was 600 (360–1,185) mg in the normal nutritional status group and 360 (127.5–660) mg in the poor nutritional status group (p < 0.001). The median overall survival from mCRPC was 30.39 months in the good nutritional status group and 11.07 months in the poor nutritional status group (p of log rank <0.001). In a multivariate model, poor nutritional status was an independent risk factor in overall survival (Hazard Ratio [HR] = 5.37, 95% Confidence Interval [CI] 3.27–8.83), together with a high metastatic volume (HR = 4.03, 95% CI 2.16–7.53) and docetaxel cumulative dosage (HR = 0.999, 95% CI 0.999–0.9998).Conclusion: Poor nutritional status with a GNRI <92 is associated with shorter progression free survival and overall survival in mCRPC patients treated with docetaxel. Metastatic volume and cumulative docetaxel dosage are also independent prognostic factors in overall survival.
Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome.Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome.Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively).Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor.
Complete resection of metastatic sites for MRCC patients, combined with targeted therapy, could provide better overall survival rates than targeted therapy alone. Poor MSKCC risk is still correlated to a poor outcome in the current targeted therapy era.
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