更新于：2024-11-01

CYP17A1 x GR

更新于：2024-11-01

基本信息

关联

项与 CYP17A1 x GR 相关的药物

Methylprednisolone/Abiraterone acetate

甲泼尼龙/醋酸阿比特龙

靶点

CYP17A1 x GR

作用机制

CYP17A1抑制剂 [+1]

在研机构

Sun Pharma ANZ Pty Ltd.

原研机构

Sun Pharma ANZ Pty Ltd.

在研适应症

激素依赖性前列腺癌 [+1]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

澳大利亚

首次获批日期2022-03-29

100 项与 CYP17A1 x GR 相关的临床结果

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100 项与 CYP17A1 x GR 相关的转化医学

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0 项与 CYP17A1 x GR 相关的专利（医药）

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项与 CYP17A1 x GR 相关的文献（医药）

2024-05-01·Asian Pacific Journal of Cancer Prevention

Characterization of Potential Target Genes of Borneol in Increasing Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer: Bioinformatics and In Vitro Studies

Article

作者: Putri, Dyaningtyas Dewi Pamungkas ; Ujiantari, Navista Sri Octa ; Hermawan, Adam ; Lestari, Intan Ayu ; Fatimah, Nurul ; Putra, I Made Rhamandana

OBJECTIVEThe long-term use of trastuzumab (TRZ), a therapeutic agent for human epidermal growth factor receptor 2 (HER2)+ breast cancer subtype (HER2+ BC), induces resistance. Borneol (BOR) exerts anticancer effects on various types of cancer. However, its anticancer effect on HER2+ BC remains unknown. This study aimed to determine the potential target genes of BOR and its effect on overcoming the resistance of HER2+ BC to TRZ.METHODSThe hub gene of BOR's potential target on HER2+ BC cells was determined via a bioinformatics approach. Resistant HCC1954 cells (HCC1954-TR) were obtained through repeated inducement of HCC1954 cancer cells with TRZ. The cells were then subjected to cytotoxic tests involving single compounds and their combinations. Then, the hub gene expression was determined using quantitative reverse-transcription polymerase chain reaction. The interaction between BOR and selected proteins was measured through molecular docking.RESULTSHub genes IL6, TNF, ESR1, IL1B, CYP19A1, AR, NR3C1, RELA, CYP17A1, and GPT were obtained via a bioinformatics approach. HCC1954-TR cells were successfully established. The TRZ-BOR combination treatment of parental HCC1954 (400 µg/mL and 25 µM) and HCC1954-TR (800 µg/mL and 100 µM) yielded considerably better results compared with BOR or TRZ alone. The expressions of AR, GPT, and ESR1 under the TRZ-BOR combination were notably different compared with those under single exposure. The molecular docking study of CYP19A1, CYP17A1, NR3C1, and IL-1β highlighted the potential interaction between BOR and such proteins.CONCLUSIONBOR improved the cytotoxic effects of TRZ on HCC1954 and HCC1954-TR cell lines, where it specifically targets AR, ESR1, and GPT genes. In addition, the BOR effect, which counteracted the resistance of HCC1954-TR cells to TRZ, was mediated by genes CYP19A1, CYP17A1, NR3C1, IL-1, and RELA. However, additional research is required to validate their role in BOR activity to circumvent the resistance of HER2+ BC to TRZ.

2022-09-01·General and Comparative Endocrinology

Impaired negative feedback and death following acute stress in glucocorticoid receptor knockout Xenopus tropicalis tadpoles

Article

作者: Anderson, Elizabeth T ; Bhawal, Ruchika ; Paul, Bidisha ; Buchholz, Daniel R ; Sterner, Zachary R ; Zhang, Sheng

Blood glucocorticoid levels are regulated by the hypothalamo-pituitary-adrenal/interrenal axis (HPA axis in mammals, HPI axis in amphibians), and negative feedback by glucocorticoid signaling is a key player in that regulation. Glucocorticoid and mineralocorticoid receptors (GR and MR) mediate negative feedback in mammals, but little is known about nuclear receptor-mediated feedback in amphibians. Because amphibians have only one corticosteroidogenic cell type responsible for glucocorticoid and mineralocorticoid production, we hypothesized that GR knockout (GRKO) tadpoles have elevated levels of glucocorticoids and mineralocorticoids as well as axis components regulating their production. We also examined the response to stress and potential for increased aldosterone signaling in GRKO tadpoles. We found that GRKO tadpoles have severe hyperactivity of the HPI axis, namely high mRNA expression levels of pomc, cyp17a1, cyp21a2, cyp11b2, and star, and high tissue content of corticosterone, aldosterone, 17-hydroxyprogesterone, 21-deoxycortisol, and progesterone. Such aberrant HPI activity was accompanied by reduced survival after acute temperature shock and shaking stress. Like mammalian models of HPA hyperactivity, GRKO tadpoles have high MR mRNA expression levels in brain, kidney, heart, and skin and high levels of the inflammatory cytokine tnf-α and the profibrotic factor tgf-β in kidneys. This study showed GR is critical for negative feedback to the amphibian HPI axis and for survival from acute stressors. This study also showed GRKO tadpoles exhibit altered expression/overproduction of regulators of salt-water homeostasis and associated biomarkers of kidney disease.

2022-04-01·The Prostate3区 · 医学

Abiraterone switches castration‐resistant prostate cancer dependency from adrenal androgens towards androgen receptor variants and glucocorticoid receptor signalling

3区 · 医学

Article

作者: Moll, J. Matthijs ; Arlt, Wiebke ; Jenster, Guido W. ; Graeser, Ralph ; de Ridder, Corina M. A. ; Hofland, Johannes ; Teubel, Wilma J. ; Taylor, Angela E. ; van Weerden, Wytske M.

AbstractIntroductionCastration‐resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signalling, which is largely driven by conversion of adrenal androgen precursors lasting after castration. Abiraterone, an inhibitor of the steroidogenic enzyme CYP17A1, has been demonstrated to reduce adrenal androgen synthesis and prolong CRPC patient survival. To study mechanisms of resistance to castration and abiraterone, we created coculture models using human prostate and adrenal tumours.Materials and MethodsCastration‐naïve and CRPC clones of VCaP were incubated with steroid substrates or cocultured with human adrenal cells (H295R) and treated with abiraterone or the antiandrogen enzalutamide. Male mice bearing VCaP xenografts with and without concurrent H295R xenografts were castrated and treated with placebo or abiraterone. Response was assessed by tumour growth and PSA release. Plasma and tumour steroid levels were assessed by LC/MS‐MS. Quantitative polymerase chain reaction determined steroidogenic enzyme, nuclear receptor and AR target gene expression.ResultsIn vitro, adrenal androgens induced castration‐naïve and CRPC cell growth, while precursors steroids for de novo synthesis did not. In a coculture system, abiraterone blocked H295R‐induced growth of VCaP cells. In vivo, H295R promoted castration‐resistant VCaP growth. Abiraterone only inhibited VCaP growth or PSA production in the presence of H295R. Plasma steroid levels demonstrated CYP17A1 inhibition by abiraterone, whilst CRPC tumour tissue steroid levels showed no evidence of de novo intratumoural androgen production. Castration‐resistant and abiraterone‐resistant VCaP tumours had increased levels of AR, AR variants and glucocorticoid receptor (GR) resulting in equal AR target gene expression levels compared to noncastrate tumours.ConclusionsIn our model, ligand‐dependent AR‐regulated regrowth of CRPC was predominantly supported via adrenal androgen precursor production while there was no evidence for intratumoural androgen synthesis. Abiraterone‐resistant tumours relied on AR overexpression, expression of ligand‐independent AR variants and GR signalling.