ABSTRACT
BACKGROUND: Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment and the therapeutic options are continuously advancing. This study aims to discover the anti-CRPC effects and underlying mechanisms of small-molecule compounds targeting topoisomerase (TOP) II and cellular components of DNA damage repair. METHODS: Cell proliferation was determined in CRPC PC-3 and DU-145 cells using anchorage-dependent colony formation, sulforhodamine B assay and flow cytometric analysis of CFSE staining. Flow cytometric analyses of propidium iodide staining and JC-1 staining were used to examine the population of cell-cycle phases and mitochondrial membrane potential, respectively. Nuclear extraction was performed to detect the nuclear localization of cellular components in DNA repair pathways. Protein expressions were determined using Western blot analysis. RESULTS: A series of azathioxanthone-based derivatives were synthesized and examined for bioactivities in which WC-A13, WC-A14, WC-A15, and WC-A16 displayed potent anti-CRPC activities in both PC-3 and DU-145 cell models. These WC-A compounds selectively downregulated both TOP IIα and TOP IIß but not TOP I protein expression. WC-A13, WC-A14, and WC-A15 were more potent than WC-A16 on TOP II inhibition, mitochondrial dysfunction, and induction of caspase cascades indicating the key role of amine-containing side chain of the compounds in determining anti-CRPC activities. Furthermore, WC-A compounds induced an increase of γH2AX and activated ATR-Chk1 and ATM-Chk2 signaling pathways. P21 protein expression was also upregulated by WC-A compounds in which WC-A16 showed the least activity. Notably, WC-A compounds exhibited different regulation on Rad51, a major protein in homologous recombination of DNA in double-stranded break repair. WC-A13, WC-A14, and WC-A15 inhibited, whereas WC-A16 induced, the nuclear translocation of Rad51. CONCLUSION: The data suggest that WC-A compounds exhibit anti-CRPC effects through the inhibition of TOP II activities, leading to mitochondrial stress-involved caspase activation and apoptosis. Moreover, WC-A13, WC-A14, and WC-A15 but not WC-A16 display inhibitory activities of Rad51-mediated DNA repair pathway which may increase apoptotic effect of CRPC cells.
Subject(s)
Antineoplastic Agents , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Antineoplastic Agents/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Cell Line, Tumor , Apoptosis , Cell Proliferation , Caspases/metabolism , Caspases/pharmacology , Caspases/therapeutic use , DNA Repair , DNA Topoisomerases, Type II/metabolism , DNA Topoisomerases, Type II/pharmacology , DNA Topoisomerases, Type II/therapeutic useABSTRACT
BACKGROUND: Depression increases the risk of cardiovascular disease (CVD). The association between antidepressant medications (ADMs) and CVD remains controversial. Hyperlipidemia is a risk factor for CVD. We conducted a nationwide population-based retrospective cohort study to examine depression and ADM use on the risk of developing hyperlipidemia. The effects of ADMs on the expression of lipogenesis-related hepatic genes were also evaluated. METHODS: We obtained data from the Longitudinal Health Insurance Database of Taiwan on patients with new-onset depression and a comparison cohort without depression. A Cox proportional hazards regression model was used to analyze the differences in the risk of developing hyperlipidemia between these two cohorts. We also examined the influence of ADMs on the expression of lipogenesis-related hepatic genes. RESULTS: After adjustment for comorbidities and confounding factors, the case group (N = 38,322) had a higher risk for hyperlipidemia than that of the control cohort (N = 38,322) [adjusted hazards ratio (aHR) =1.16]. Patients with depression who did not receive ADM therapy exhibited a significantly higher risk of hyperlipidemia (aHR = 1.61). However, in patients with depression treated with ADMs, the risk of developing hyperlipidemia was significantly lowered compared to the patients without ADMs (all aHR < 0.81). Gene expression analysis indicated that ADMs downregulated the expression of lipogenesis-related hepatic genes. LIMITATIONS: Unmeasured confounding risk factors for hyperlipidemia might not have been included in the study. CONCLUSIONS: ADMs reduced hyperlipidemia risk in patients with depression, partly by downregulating the expression of lipogenesis-related genes and improving the patients' lipid profiles. Early diagnosis and management of hyperlipidemia would further facilitate the prevention of CVD.
Subject(s)
Hyperlipidemias , Antidepressive Agents , Cohort Studies , Comorbidity , Depression/epidemiology , Depression/genetics , Gene Expression , Humans , Hyperlipidemias/epidemiology , Hyperlipidemias/genetics , Incidence , Lipogenesis/genetics , Proportional Hazards Models , Retrospective Studies , Risk Factors , Taiwan/epidemiologyABSTRACT
Considering the birefringence of the gain medium, we propose a selection rule for designing cavity configurations that enable the generation of radially and azimuthally polarized laser beams with a low beam quality factor, i.e., high beam quality. Using this rule, all stable regions can support cylindrical vector (CV) beams by using the position of the end mirror as the tuning parameter to vary the cavity configuration. Such cavity configurations tend to sustain the fundamental or lowest-order CV beam, and radially or azimuthally polarized beams can be obtained simply by varying the tuning parameter. Based on experimental measurements of the beam quality factor and polarization characteristics, we verified our analyses and simulations for a four-element laser system.