Cancer Cell International
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2019
·Vol. 19
·期 1
·1-10
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IF 3.439
Han Jingli,Zhang Junhua,Zhang Wei,Zhang Dalei,Li Ying,Zhang Jinsong,Zhang Yaqun,Diao Tongxiang,Cui Luwei,Li Wenqing,Xiao Fei,Liu Ming,Zou Lihui
Background Abiraterone and MDV3100 are two effective anticancer agents for prostate cancer, however, the mechanism of their downstream action remains undefined.Methods A dual fluorescent biosensor plasmid was transfected in LNCaP cells to measure mitophagy. The DNA of LNCaP cells was extracted and performed with quantitative real-time PCR to detect mitochondrial DNA copy number. JC-1 staining was utilized to detect the mitochondrial membrane potential and electron microscope was performed to analyze mitochondrial morphology. Moreover, the protein levels of mitochondrial markers and apoptotic markers were detected by western blot. At last, the proliferation and apoptosis of LNCaP cells were analyzed with CCK-8 assay and flow cytometry after abiraterone or MDV3100 treatment.Results Mitophagy was induced by abiraterone and MDV3100 in LNCaP cells. The low expression level of mitochondrial DNA copy number and mitochondrial depolarization were further identified in the abiraterone or MDV3100 treatment groups compared with the control group. Besides, severe mitochondria swelling and substantial autophagy-lysosomes were observed in abiraterone- and MDV3100-treated LNCaP cells. The expression of mitochondria-related proteins, frataxin, ACO2 and Tom20 were significantly downregulated in abiraterone and MDV3100 treated LNCaP cells, whereas the expression level of inner membrane protein of mitochondria (Tim23) was significantly upregulated in the same condition. Moreover, the proliferation of LNCaP cells were drastically inhibited, and the apoptosis of LNCaP cells was increased in abiraterone or MDV3100 treatment groups. Meanwhile, the addition of mitophagy inhibitor Mdivi-1 (mitochondrial division inhibitor 1) could conversely elevate proliferation and constrain apoptosis of LNCaP cells.Conclusion sOur results prove that both abiraterone and MDV3100 inhibit the proliferation, promote the apoptosis of prostate cancer cells through regulating mitophagy. The promotion of mitophagy might enhance the efficacy of abiraterone and MDV3100, which could be a potential strategy to improve chemotherapy with these two reagents.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Pharmaceutics
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2022
·Vol. 14
·期 6
·1134
·
IF 6.525
Yuanfen Liu,Yuqi Li,Pengcheng Xu,Yan Shen,Baoqiang Tang,Qiyue Wang
Abiraterone acetate is a prodrug of abiraterone used in combination with prednisone as a standard therapeutic strategy for hormone-resistant prostate cancer (mCRPC). Due to the poor solubility and permeability, the release and absorption of abiraterone acetate are low and reduce its bioavailability. In this project, abiraterone acetate tablets prepared using nanocrystal technology were developed to overcome the drawbacks of normal tablets by enhancing in vitro dissolution rate and oral bioavailability. The abiraterone acetate nanocrystal suspensions were prepared by top-down wet milling method using a planetary ball mill with the mixture of Poloxamer 407 and Poloxamer 188 as the optimized stabilizer at a ratio of 7:1. The optimized nanocrystals were freeze-dried and characterized using DLS, TEM, DSC, and XRD. The abiraterone acetate nanocrystal tablets significantly improve the in vitro dissolution rate of abiraterone acetate compared to raw materials. Although exhibiting a similar dissolution rate compared to the Zytiga®tablets, the nanocrystal tablets significantly improve the oral bioavailability with Cmaxand AUC0–tbeing 3.51-fold and 2.80-fold higher, respectively, in the pharmacokinetic study. The present data indicate that nanocrystal is a promising strategy for improving the dissolution and bioavailability of abiraterone acetate.Keywords:abiraterone acetate;nanocrystal;poloxamer;dissolution;oral bioavailability
研究领域:
药剂学
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肿瘤学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2023
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IF 5.1
Haoyang Xu,Jiaqi Liu,Xiangkai Li,Jiawei Li,Xiao Lin,Zhuowei Li,Tong Dou,Li Gao,Rong Li,Keng Po Lai
Prostate cancer is the second most common cause of cancer-related deaths in men and is common in most developed countries. Androgen deprivation therapy (ADT) that uses abiraterone acetate (AA) is an effective second-line treatment for prostate cancer. However, approximately 20–40% of patients develop primary resistance to abiraterone post-treatment. In this study, we aimed to understand the molecular mechanisms underlying the development of abiraterone resistance in prostate cancer cells and the potential use of black phosphorus nanosheets (BPNS) for treating abiraterone-resistant prostate cancer. We first established abiraterone-resistant prostate cancer PC-3 cells and found that these cells have higher migration ability than normal prostate cancer cells. Using comparative transcriptomic and bioinformatics analyses between abiraterone-sensitive PC-3 and abiraterone-resistant PC-3 cells, we highlighted the differentially expressed genes (DEGs) involved in the biological processes related to prostate gland morphogenesis, drug response, immune response, angiogenesis. We further studied the therapeutic effects of BPNS. Our results show that BPNS reduced the proliferation and migration of abiraterone-resistant PC-3 cells. Bioinformatics analysis, including gene ontology, Kyoto encyclopedia of genes and genomes enrichment analysis, and ingenuity pathway analysis (IPA) of the DEGs, suggested that BPNS treatment controlled cancer cell proliferation, metastasis, and oncogenic signaling pathways. Furthermore, the IPA gene network highlighted the involvement of the MMP family, ATF, and notch families in the anti-prostate cancer function of BPNS. Our findings suggest that BPNS may have a chemotherapeutic function in treating abiraterone-resistant prostate cancer.
研究领域:
肿瘤学
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分子生物学
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生物信息学
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DOI
PubMed
高影响因子
Frontiers in Oncology
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2021
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IF 6.244
Hu Zengchun,Cheng Chuandong,Wang Yue,Chen Tianrui,Tu Junhong,Niu Chaoshi,Xing Rong,Wang Yang,Xu Yinghui
Neuroblastoma is the most common extracranial neuroendocrine tumor in childhood. Although many studies have tried to find effective treatments, there are still numerous limitations in current clinical targeted therapy. So, it is important to find new therapeutic targets and strategies from a new perspective. Our previous study reported that the androgen receptor (AR) promotes the growth of neuroblastoma in vitro and in vivo. Based on documentary investigation, we postulated that the AR–SCAP–SREBPs-CYP17/HMGCR axis may regulate cholesterol and androgens synthesis and form a positive enhancement loop promoting NB progression. Clinical samples and Oncomine database analysis proved the activation of AR–SCAP–SREBPs-CYP17/HMGCR axis in neuroblastoma. The combination of inhibitors of HMGCR (statins) and CYP17A1 (abiraterone acetate) showed synergistic effect that significantly inhibited the proliferation and migration with decreased expression of related genes detected in vitro and in vivo suggesting the dual-targeted therapy had the potential to inhibit the progression of neuroblastoma in spite of its MYCN status. This study provides new ideas for clinical treatment of neuroblastoma with efficacy and reduced toxicity.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CANCER LETTERS
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2024
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IF 9.1
Chunyu Liu,Jiawei Chen,Yukun Cong,Kang Chen,Haoran Li,Qingliu He,Liang Chen,Yarong Song,Yifei Xing
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2025
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IF 4.3
Fulin Bi,Yan Lin,Baohong Zhang,Zishan Chen,Jixia Li,Tong Yuan,Jin Yang
Prodrugs with enzymatic activation requirements, such as the weakly basic biopharmaceutical classification system (BCS) class IV compound abiraterone acetate (ABA), face considerable bioequivalence (BE) risks owing to their pH-dependent solubility, food effects, and variable intestinal hydrolysis. This study established clinically relevant dissolution specifications for ABA using biorelevant dissolution and physiologically based biopharmaceutics modelling (PBBM). Two dissolution methods, two-stage (gastrointestinal transfer simulation) and single-phase (biorelevant media), were evaluated under fasted and fed conditions. Clinical BE studies revealed non-BE for formulation A (fasted, N = 39) but compliance for formulation B (fasted/fed, N = 40). Two-stage dissolution highlighted supersaturation dynamics, with fed-state media (FeSSIF-V2) enhancing solubility by >10-fold compared to fasted conditions. Although this method is biopredictive, its complexity limits its practicality. Single-phase dissolution using biorelevant media balances discriminative power and operational feasibility for quality control. Permeability studies identified the active metabolite abiraterone as the absorption driver (apparent permeability coefficient: 1.55 × 10 −5 vs. 8.91 × 10 − ⁶ cm/s for ABA). PBBM integrating hydrolysis kinetics, food effects, and first-pass metabolism predicted clinical pharmacokinetics with a prediction error of <20 %. Virtual BE trials defined a dissolution “safe space” for bioequivalence under both fasted/fed states. This study demonstrates that combining biorelevant dissolution with mechanistic modelling mitigates BE risks for high-variability prodrugs. This single-phase approach offers a scalable and physiologically aligned strategy for guiding the generic development of complex formulations with food-dependent absorption variability.
研究领域:
药剂学
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生物药剂学
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药代动力学
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药物研发
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计算建模
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溶出度测试
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PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHIC SCIENCE
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2021
·Vol. 60
·期 2
·105-110
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IF 1.618
Zhong ZhenHua,Chen YuPing,Xia HongYing,Chen ZhenZhen,Cheng QiZhen
A sensitive and selective gas chromatography–tandem mass spectrometry method was developed for the identification and quantification of five potential genotoxic impurities (PGIs), i.e., chloromethane, 2-chloropropane, 2-bromopropane, 4-chloro-1-butanol and diethyl sulfate, in abiraterone acetate. The method was validated according to the International Council for Harmonisation (ICH) guidelines. The linearity was established for the concentration range of 30–480 ng/mL (2-chloropropane, 2-bromopropane, 4-chloro-1-butanol and diethyl sulfate) and 90–1440 ng/mL (chloromethane). The correlation coefficient of each PGIs was >0.995. The extraction recoveries ranged from 90.49 to 106.79% for the five PGIs. The quantitation limit, detection limit, accuracy, precision, repeatability and stability of the method demonstrated that the method was an adequate quality control tool for quantitation and identification of chloromethane, 2-chloropropane, 2-bromopropane, 4-chloro-1-butanol and diethyl sulfate at trace levels in drug substances and drug products.
研究领域:
药物分析
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分析化学
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药品质量控制
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）