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1.
Acta Pharmacol Sin ; 44(10): 2113-2124, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37225847

ABSTRACT

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.


Subject(s)
Enhancer of Zeste Homolog 2 Protein , Lymphoma, Large B-Cell, Diffuse , Humans , Benzamides/pharmacology , Benzamides/therapeutic use , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Enhancer of Zeste Homolog 2 Protein/drug effects , Enzyme Inhibitors/pharmacology , Homeostasis , Lymphoma, Large B-Cell, Diffuse/metabolism , Receptors, Transferrin/metabolism , Iron/metabolism
2.
Medicine (Baltimore) ; 102(10): e33101, 2023 Mar 10.
Article in English | MEDLINE | ID: mdl-36897714

ABSTRACT

BACKGROUND: Postoperative pain is one of the most feared complications of total knee arthroplasty. Recently, randomized controlled trials have compared the efficacy of duloxetine in patients undergoing total knee arthroplasty. However, there is no definite answer as to the efficacy and safety of duloxetine. METHODS: Randomized controlled trials about relevant studies were searched from PubMed (1996 to July 2022), Embase (1996 to July 2022), and Cochrane Library (CENTRAL, July 2022). RESULTS: Six high-quality studies containing 532 patients met the inclusion criteria. Results show patients in the duloxetine group had better performance in terms of visual analog scale (P < .05), equivalent morphine consumption (P < .05), and length of stay (P < .05). CONCLUSION: Duloxetine can be used to reduce pain after knee arthroplasty in selected patients.


Subject(s)
Arthroplasty, Replacement, Knee , Pain Management , Humans , Arthroplasty, Replacement, Knee/adverse effects , Duloxetine Hydrochloride , Pain Management/methods , Pain, Postoperative/etiology , Randomized Controlled Trials as Topic
3.
Cell Death Dis ; 13(8): 748, 2022 08 29.
Article in English | MEDLINE | ID: mdl-36038549

ABSTRACT

Tumor associated macrophages (TAMs) play an important role in tumorigenesis, development and anti-cancer drug therapy. However, very few epigenetic compounds have been elucidated to affect tumor growth by educating TAMs in the tumor microenvironment (TME). Herein, we identified that EZH2 performs a crucial role in the regulation of TAMs infiltration and protumoral polarization by interacting with human breast cancer (BC) cells. We showed that EZH2 inhibitors-treated BC cells induced M2 macrophage polarization in vitro and in vivo, while EZH2 knockdown exhibited the opposite effect. Mechanistically, inhibition of EZH2 histone methyltransferase alone by EZH2 inhibitors in breast cancer cells could reduce the enrichment of H3K27me3 on CCL2 gene promoter, elevate CCL2 transcription and secretion, contributing to the induction of M2 macrophage polarization and recruitment in TME, which reveal a potential explanation behind the frustrating results of EZH2 inhibitors against breast cancer. On the contrary, EZH2 depletion led to DNA demethylation and subsequent upregulation of miR-124-3p level, which inhibited its target CCL2 expression in the tumor cells, causing arrest of TAMs M2 polarization. Taken together, these data suggested that EZH2 can exert opposite regulatory effects on TAMs polarization through its enzymatic or non-enzymatic activities. Our results also imply that the effect of antitumor drugs on TAMs may affect its therapeutic efficacy, and the combined application with TAMs modifiers should be warranted to achieve great clinical success.


Subject(s)
Breast Neoplasms , Breast Neoplasms/pathology , Cell Line, Tumor , Chemokine CCL2/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Female , Humans , Macrophages/metabolism , Tumor Microenvironment/genetics , Tumor-Associated Macrophages , Up-Regulation
4.
Acta Pharmacol Sin ; 42(6): 998-1004, 2021 Jun.
Article in English | MEDLINE | ID: mdl-32918045

ABSTRACT

The ROS1 fusion kinase is an attractive antitumor target. Though with significant clinical efficacy, the well-known first-generation ROS1 inhibitor (ROS1i) crizotinib inevitably developed acquired resistance due to secondary point mutations in the ROS1 kinase. Novel ROS1is effective against mutations conferring secondary crizotinib resistance, especially G2032R, are urgently needed. In the present study, we evaluated the antitumor efficacy of SAF-189s, the new-generation ROS1/ALK inhibitor, against ROS1 fusion wild-type and crizotinib-resistant mutants. We showed that SAF-189s potently inhibited ROS1 kinase and its known acquired clinically resistant mutants, including the highly resistant G2032R mutant. SAF-189s displayed subnanomolar to nanomolar IC50 values against ROS1 wild-type and mutant kinase activity and a selectivity vs. other 288 protein kinases tested. SAF-189s blocked cellular ROS1 signaling, and in turn potently inhibited the cell proliferation in HCC78 cells and BaF3 cells expressing ROS1 fusion wild-type and resistance mutants. In nude mice bearing BaF3/CD74-ROS1 or BaF3/CD74-ROS1G2032R xenografts, oral administration of SAF-189s dose dependently suppressed the growth of both ROS1 wild-type- and G2032R mutant-driven tumors. In a patient-derived xenograft model of SDC4-ROS1 fusion NSCLC, oral administration of SAF-189s (20 mg/kg every day) induced tumor regression and exhibited notable prolonged and durable efficacy. In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1G2032R. Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Crizotinib/therapeutic use , Female , Humans , Mice, Nude , Mutation , Neoplasms/enzymology , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
5.
Acta Pharmacol Sin ; 40(12): 1587-1595, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31171828

ABSTRACT

Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.


Subject(s)
Acrylamides/pharmacology , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Polycomb Repressive Complex 2/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation , Enhancer of Zeste Homolog 2 Protein/metabolism , ErbB Receptors/antagonists & inhibitors , Humans , MicroRNAs/metabolism , Polycomb Repressive Complex 2/metabolism , Protein Binding/drug effects , Up-Regulation
6.
Acta Pharmacol Sin ; 39(3): 415-424, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29119969

ABSTRACT

BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumor-bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy.


Subject(s)
Bufanolides/metabolism , Dipeptides/metabolism , Gelatinases/metabolism , Membrane Proteins/metabolism , Piperazines/metabolism , Prodrugs/metabolism , Serine Endopeptidases/metabolism , Animals , Bufanolides/chemistry , Bufanolides/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Dipeptides/chemistry , Dipeptides/pharmacology , Endopeptidases , Humans , Hydrolysis , Mice , Piperazines/chemistry , Piperazines/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Xenograft Model Antitumor Assays
7.
Eur J Med Chem ; 126: 1083-1106, 2017 Jan 27.
Article in English | MEDLINE | ID: mdl-28039836

ABSTRACT

We present herein the discovery and development of novel and potent Nek2 inhibitors with distinctive in vitro and in vivo antitumor activity based on an imidazo[1,2-a]pyridine scaffold. Our studies identified a nonlinear SAR for activity against both Nek2 and cancer cells. Bioisostere and structure-based design techniques were employed to identify compounds 42c (MBM-17, IC50 = 3.0 nM) and 42g (MBM-55, IC50 = 1.0 nM), which displayed low nanomolar activity and excellent selectivity for Nek2. Both compounds effectively inhibited the proliferation of cancer cells by inducing cell cycle arrest and apoptosis. Importantly, the salts form of these two compounds (MBM-17S and MBM-55S) significantly suppressed tumor growth in vivo without apparent toxicity based on appearance and changes in body weight. In summary, MBM-17 and MBM-55 displayed the potential for substantial therapeutic application in cancer treatment.


Subject(s)
Drug Design , NIMA-Related Kinases/antagonists & inhibitors , Nitrazepam/chemistry , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Male , Mice , Molecular Docking Simulation , NIMA-Related Kinases/chemistry , NIMA-Related Kinases/metabolism , Polyploidy , Protein Conformation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
8.
Huan Jing Ke Xue ; 38(9): 3762-3768, 2017 Sep 08.
Article in Chinese | MEDLINE | ID: mdl-29965257

ABSTRACT

Pyrite was used as catalyst to degrade Microcystin-LR (MC-LR) at pH 6.8 under visible light irradiation (λ>420 nm). X-ray diffraction (XRD) and scanning electron microscope (SEM) characterization showed that pyrite had the layered structure. The ion state of pyrite before and after the reaction was identified using X-Ray Photoelectron Spectroscopy (XPS), confirming the conversion process of Fe(Ⅱ) to Fe(Ⅲ) on the sulfur defect sites. Electron Spin Resonance (ESR) test showed that pyrite photochemical reaction produced hydroxyl radical (·OH). The results of high performance liquid chromatography (HPLC) and liquid chromatograph-mass spectrometer (LC-MS) showed that visible light irradiation could effectively activate pyrite to degrade MC-LR. The degradation rate of MC-LR reached 100% after 10 hours and the mineralization rate reached 60% after 20 hours. The two reaction pathways of photochemical oxidation of MC-LR by pyrite were discussed.


Subject(s)
Iron/chemistry , Microcystins/chemistry , Photochemical Processes , Sulfides/chemistry , Catalysis , Ferric Compounds , Marine Toxins , Oxidation-Reduction
9.
Chemistry ; 19(9): 3224-9, 2013 Feb 25.
Article in English | MEDLINE | ID: mdl-23325602

ABSTRACT

The band structure of multicomponent semiconductor photocatalysts, as well as their reactivity distinction under different wavelengths of light, is still unclear. BiOBr, which is a typical multicomponent semiconductor, may have two possible valence-band structures, that is, two discrete valence bands constructed respectively from O 2p and Br 4p orbitals, or one valence band derived from the hybridization of these orbitals. In this work, aqueous photocatalytic hydroxylation is applied as the probe reaction to investigate the nature and reactions of photogenerated holes in BiOBr. Three organic compounds (microcystin-LR, aniline, and benzoic acid) with different oxidation potentials were selected as substrates. Isotope labeling (H(2)(18)O as the solvent) was used to determine the source of the O atom in the hydroxyl group of the products, which distinguishes the contribution of different hydroxylation pathways. Furthermore, a spin-trapping ESR method was used to quantify the reactive oxygen species ((.)OH and (.)OOH) formed in the reaction system. The different isotope abundances of the hydroxyl O atom of the products formed, as well as the reverse trend of the (.)OH/(.)OOH ratio with the oxidative resistance of the substrate under UV and visible irradiation, reveal that BiOBr has two separate valence bands, which have different oxidation ability and respond to UV and visible light, respectively. This study shows that the band structure of semiconductor photocatalysts can be reliably analyzed with an isotope labeling method.

10.
Guang Pu Xue Yu Guang Pu Fen Xi ; 28(8): 1887-90, 2008 Aug.
Article in Chinese | MEDLINE | ID: mdl-18975826

ABSTRACT

The reaction conditions for the determination of bovine serum albumin (BSA) using o-hydroxyphenylfluorone (o-HPF) as fluorescence probe reagent were studied. In the B-R medium at pH 7.90, o-HPF could react with BSA, producing a stable complex compound which resulted in fluorescent quenching of this binary system. The quantitative assay was carried out based on the relation between the degree of fluorescent quenching and the additional amount of BSA. The method has advantages of good selectivity, stability and simplicity. The linear range of o-HPF fluorescence spectrophotometric method was 1.32-18.54 microg x mL(-1). Moreover, the mechanism of the reaction BSA and o-HPF was discussed, and the quenching constant, and the ther modynamics constant of the fluorescence effects were calculated. The results showed that the nonconvalent binding forces were the binding force between o-HPF and BSA, and the quenching of BSA to o-HPF was probably a single static quenching process.


Subject(s)
Fluoresceins/chemistry , Fluorescent Dyes/chemistry , Serum Albumin, Bovine/analysis , Spectrometry, Fluorescence , Animals , Cattle , Fluoresceins/analysis , Fluorescent Dyes/analysis , Serum Albumin, Bovine/chemistry
11.
Guang Pu Xue Yu Guang Pu Fen Xi ; 28(6): 1336-9, 2008 Jun.
Article in Chinese | MEDLINE | ID: mdl-18800717

ABSTRACT

The reactions were studied for the determination of bovine serum albumin (BSA) using o-hydroxyphenylfluorone (o-HPF) as fluorescence probe reagent with fluorescence spectrophotometry. In the B-R medium, o-HPF reacts with BSA to form the stable complex compound. The reaction system of o-HPF and BSA was binary system, and the method for the determination of BSA was of good selectivity and stability and simplicity. The linear range of o-HPF fluorescence spectrophotometric method was 1.32-18.54 microg x mL(-1) The quenching constant and thermodynamics constant of the fluorescence effects between BSA and o-HPF were calculated. The results showed that the non-covalent binding forces were the binding force between o-HPF and BSA.


Subject(s)
Fluorescent Dyes/chemistry , Serum Albumin, Bovine/analysis , Spectrometry, Fluorescence/methods , Hydrogen-Ion Concentration , Temperature , Thermodynamics
12.
Guang Pu Xue Yu Guang Pu Fen Xi ; 28(4): 917-21, 2008 Apr.
Article in Chinese | MEDLINE | ID: mdl-18619329

ABSTRACT

The present paper introduces a new method using spectrofluorimetric analysis to determine the concentration of hydrogen peroxide in rainwater. In this method, an oxidation reaction is conducted between o-phenylenediamine (OPDA) and hydrogen peroxide in the buffer medium of NaAc-HAc at pH 4. 48 to form a new product 2,3-diaminophenazine (DAPN). Then the fluorescence intensity of DAPN is measured and 426 and 554 nm are chosen as the excitation and emission wavelengths. Therefore, with the foreknown concentration of input hydrogen peroxide, a series of fluorescence intensities of DAPN are acquired according to a series of different concentration of hydrogen peroxide as input, greatly improving the selectivity and sensibility of the system. A relationship between the input concentration of hydrogen peroxide and the fluorescence intensity of DAPN is then obtained using a linear regression. Results show that fluorescence intensity of DAPN is in proportion to the increase in the concentration of hydrogen peroxide in the range of 9.0 x 10(-7) -3.56 x 10(-5) mol x L(-1) almost linearly. The linear equation is F = 1.15c (micromol x L(-1))+398.6 (r = 0.999 1) and the detection limit is 2.7 x10(-7) mol x L(-1) (n = 11). The relative standard deviation of 11 parallel measurements with the concentration of H2O2 at 7.5 x 10(-6) and 3.0 x 10(-5) mol x L(-1), is 2.2 and 1.0%, respectively. Results from DPD method was used to verify this method. The interference of foreign iron was studied. Compared to the traditional methods, this binary system has a simplified operation and high sensitivity. The proposed method has been successfully applied to determine the concentration of hydrogen peroxide in rainwater.


Subject(s)
Fluorometry/methods , Hydrogen Peroxide/analysis , Rain/chemistry , Water/chemistry
13.
J Environ Sci (China) ; 19(1): 97-102, 2007.
Article in English | MEDLINE | ID: mdl-17913161

ABSTRACT

The photocatalytic degradation of dye pollutant sulforhodamine-B (SRB) in aqueous titanium dioxide (TiO2) dispersions was examined under three lighting regimes: UV light (330 nm450 nm), all investigated at pH=2.5. Total organic carbon (TOC) and chemical oxygen demand (COD(Cr)) assays show that the degradation rate of SRB is much higher when irradiated with UV and sunlight compared with visible light. The temporal concentration changes of SRB illustrated a first-order reaction and the rate constant, k, is 0.197 min(-1), 0.152 min(-1), 0.027 min(-1), respectively, under the three lighting conditions. The final mineralized products were amine compounds identified by infrared spectrophotometry. When irradiated with visible light, the photocatalytic degradation rate could be improved by lowering the H202 concentration and inhibited by increasing the H2O2 concentration, but results contrary to the above were obtained when UV light was used for irradiation.


Subject(s)
Light , Rhodamines/chemistry , Catalysis , Hydrogen Peroxide/chemistry , Kinetics , Photochemistry
14.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 36(3): 255-60, 2007 05.
Article in Chinese | MEDLINE | ID: mdl-17571308

ABSTRACT

OBJECTIVE: To evaluate the antiproliferative activity of 3-(2-chlorophenyl)-1-(2-hydroxy-4, 6-dimethoxy-3-((ethyl(methyl) amino) methyl) phenyl) prop-2-en-1-one (DMF) against human androgen-independent prostate cancer PC3 cells in vitro and its underlying mechanisms. METHODS: The cytotoxic effect of DMF on PC3 cells was measured by MTT assay. Induction of apoptosis was assessed by propidium iodide staining and flow cytometric analysis. Changes of mitochondrial membrane potential (DeltaPsim) were detected by JC-1 staining. The levels of apoptosis related proteins were analyzed by Western blot. RESULTS: DMF exhibited high efficiency on cell growth inhibition in PC3 cells with an IC50 value of (9.5 +/- 0.2)micromol/L. Flow cytometric analysis indicated that DMF could induce apoptosis in PC3 cells. A significant decrease of mitochondrial membrane potential was observed in PC3 cells treated with DMF, which was in a time- and dose-dependent manner. The results of Western blot indicated that DMF induced the activation of caspase-3, increased the ratio of Bax/Bcl-2 and downregulated the expression of phosphate-p38. CONCLUSION: DMF is a potential compound against PC3 cells and the mitochondrial pathway might be involved in DMF-induced apoptosis in PC3 cells.


Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Chlorobenzenes/pharmacology , Growth Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Blotting, Western , Caspase 3/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Flavonoids/pharmacology , Flow Cytometry , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Piperidines/pharmacology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , bcl-2-Associated X Protein/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
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