Dietary phytochemicals are excellent ROS-modulating agents and have been shown to effectively enhance ROS levels beyond toxic threshold in cancer cells to ensure their selective killing while leaving normal cells unscathed. Here we demonstrate that hydroxychavicol (HC), extracted and purified from Piper betel leaves, significantly inhibits growth and proliferation via ROS generation in human prostate cancer, PC-3 cells. HC perturbed cell-cycle kinetics and progression, reduced clonogenicity and mediated cytotoxicity by ROS-induced DNA damage leading to activation of several pro-apoptotic molecules. In addition, HC treatment elicited a novel autophagic response as evidenced by the appearance of acidic vesicular organelles and increased expression of autophagic markers, LC3-IIb and beclin-1. Interestingly, quenching of ROS with tiron, an antioxidant, offered significant protection against HC-induced inhibition of cell growth and down regulation of caspase-3, suggesting the crucial role of ROS in mediating cell death. The collapse of mitochondrial transmembrane potential by HC further revealed the link between ROS generation and induction of caspase-mediated apoptosis in PC-3 cells. Our data showed remarkable inhibition of prostate tumor xenografts by ~72% upon daily oral administration of 150 mg/kg bw HC by quantitative tumor volume measurements and non-invasive real-time bioluminescent imaging. HC was well-tolerated at this dosing level without any observable toxicity. This is the first report to demonstrate the anti-prostate efficacy of HC in vitro and in vivo, which is perhaps attributable to its selective prooxidant activity to eliminate cancer cells thus providing compelling grounds for future preclinical studies to validate its potential usefulness for prostate cancer management.
Plant extracts, a concoction of bioactive non-nutrient phytochemicals, have long served as the most significant source of new leads for anticancer drug development. Explored for their unique medicinal properties, the leaves of Piper betel, an evergreen perennial vine, are a reservoir of phenolics with antimutagenic, antitumor and antioxidant activities. Here, we show that oral feeding of betel leaf extract (BLE) significantly inhibited the growth of human prostate xenografts implanted in nude mice compared with vehicle-fed controls. To gain insights into the 'active principles', we performed a bioactivity-guided fractionation of methanolic BLE employing solvents of different polarity strengths using classical column chromatography. This approach yielded 15 fractions, which were then pooled to 10 using similar retention factors on thin-layer chromatographs. Bioactivity assays demonstrated that one fraction in particular, F2, displayed a 3-fold better in vitro efficacy to inhibit proliferation of prostate cancer cells than the parent BLE. The presence of phenols, hydroxychavicol (HC) and chavibetol (CHV), was confirmed in F2 by nuclear magnetic resonance, high-performance liquid chromatography and mass spectroscopy. Further, the HC containing F2 subfraction was found to be ~8-fold more potent than the F2 subfraction that contained CHV, in human prostate cancer PC-3 cells as evaluated by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Removing CHV from F2 remarkably decreased the IC50 of this fraction, indicating that HC is perhaps the major bioactive constituent, which is present to an extent of 26.59% in BLE. These data provide evidence that HC is a potential candidate for prostate cancer management and warrants further preclinical evaluation.
Purpose: Commonly prescribed medications among patients with comorbid diabetes mellitus and hypertension include ARBs and ACEIs. However, these medications are associated with suboptimal adherence leading to inadequately controlled blood pressure. Unlike traditional single estimates of proportion of days covered (PDC), group-based trajectory modeling (GBTM) can graphically display the dynamic nature of adherence. The objective of this study was to evaluate adherence using GBTMs among patients prescribed ACEI/ARBs and identify predictors associated with each adherence trajectory. Patients and Methods: Patients with an ACEI/ARBs prescription were identified between July 2017 and December 2017 using a Medicare Advantage dataset. PDC was used to measure monthly patient adherence during the one-year follow-up period. The monthly PDC was added to a logistic group-based trajectory model to provide distinct patterns of adherence. Further, a multinomial logistic regression was conducted to determine predictors of each identified adherence trajectory. Predictors included various socio-demographic and clinical patient characteristics. Results: A total of 22,774 patients were included in the analysis and categorized into 4 distinct adherence trajectories: rapid decline (12.6%); adherent (58.5%); gaps in adherence (12.2%), and gradual decline (16.6%). Significant predictors associated with all lower adherence trajectories included 90 days refill, >2 number of other medications, ≥1 hospitalizations, and prevalent users. Significant predictors associated with the rapid decline trajectory included male sex, comorbidities, and increased CMS risk score. Further, significant predictors associated with the gaps in adherence trajectory included increasing age, and comorbidities. Lastly, significant predictors associated with the gradual decline trajectory included increasing age, no health plan subsidy, comorbidities, and increasing CMS risk score. Conclusion: Identifying various patient characteristics associated with non-adherent trajectories can guide the development of tailored interventions to enhance adherence to ACEI/ARBs.
BACKGROUND: Approximately 32% (75 million) of adults have hypertension in the United States, leading to 1,100 daily deaths and costing more than $48 billion annually in medical expenditures. Approximately 25% of patients with hypertension require triple combination therapy to reach recommended blood pressure. Currently, only 3 single-pill triple-combination therapies are available in the market for the treatment of hypertension. Medication adherence has become a major concern for the health care system, and nonadherence is associated with higher risks of morbidity and mortality.OBJECTIVE: To compare medication adherence rates among single-pill triple-combination therapy, free triple-combination therapy, and fixeddose dual-combination therapy plus a third agent in hypertensive patients enrolled in a Medicare Advantage prescription drug plan using 2 adherence definitions.METHODS: A retrospective cohort study was conducted using Cigna-HealthSpring's medical claims database from January 2014 to December 2016. Antihypertensive combination therapy users were classified into a single-pill triple-combination group, a fixed-dose dual-combination plus a third agent group, and a free triple-combination group. Adherence rates using proportion of days covered (PDC) were calculated for each group within a 1-year follow-up period using 2 definitions: a strict one requiring all antihypertensive agents during follow-up and a more relaxed definition requiring any antihypertensive agent during follow-up. Descriptive statistics were examined, and group differences were assessed using chi-square and analysis of variance. Multivariate logistic regression was conducted to control confounders of adherence using both definitions. RESULTS: 10,836 triple-combination users were identified. In the multivariate model using the first definition, fixed-dose dual-combination plus a third agent was significantly associated with lower adherence compared with single-pill triple therapy (OR = 0.177; 95% CI = 0.119-0.263; P < 0.001). No significant difference was detected between single-pill triple-combination therapy in comparison with free-combination therapy. In the multivariate model using the second definition, fixed-dose dual-combination plus a third agent and free-combination therapy were significantly associated with better adherence in comparison with single-pill triple combination therapy (OR = 3.62, 95% CI = 2.59-5.05; OR = 4.31, 95% CI = 2.15-8.64, respectively). Younger age, female gender, language (Spanish), some comorbidities, and previous hospitalization had a negative effect on adherence. CONCLUSIONS: Measuring adherence to multiple concurrent regimens is complicated and different adherence definitions can result in significant variations in adherence measures. Future research evaluating clinical outcomes with various definitions is needed.
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