A Single-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of 3,3'-Diindolylmethane (BR-DIM) in Patients With Systemic Lupus Erythematosus (SLE)

This is a single center study of patients with inactive or mild SLE being performed to determine the safety, tolerability, and pharmacodynamics of DIM.

开始日期2016-01-01

申办/合作机构

Northwell Health, Inc.

NCT01612910 / Withdrawn临床2期IIT

A Pilot Study of BR-DIM in Women With Stage II-III, Triple Negative, and Androgen Receptor Positive, Invasive Breast Cancer, Who Have Residual Disease Following Surgical Resection After Neoadjuvant Chemotherapy

This study is being done to find out whether a nutritional supplement, called BioResponse-DIM (BR-DIM [oral microencapsulated diindolylmethane]), improves the survival for women who have residual cancer cells following surgery after chemotherapy for breast cancer. BR-DIM is an active ingredient in cruciferous vegetables (broccoli, brussels sprouts and cauliflower). Consumption of these vegetables has been associated with a decreased risk in several cancers. Researchers also hope to find out whether different biomarkers (also called "markers") in the blood predict the chance of breast cancer returning. BR-DIM is thought to be effective in treating stage II-III breast cancer that is triple negative, AR positive (+), and where there is residual cancer cells in the breast after chemotherapy.

开始日期2012-06-01

申办/合作机构

Barbara Ann Karmanos Cancer Institute

[+1]

NCT00450229 / Completed临床1期IIT

Phase Ib Placebo-Controlled Trial of Diindolylmethane (BR-DIM) in the Study of the Modulation of Intermediate Endpoint Markers in Patients With Prostate Cancer Who Are Undergoing Prostatectomy

Giving diindolylmethane, a substance found in cruciferous vegetables, may help doctors learn more about how diindolylmethane is used by the body. This randomized phase I trial is studying the side effects and best dose of diindolylmethane compared with a placebo in treating patients undergoing radical prostatectomy for stage I or stage II prostate cancer.

开始日期2007-02-01

申办/合作机构

National Cancer Institute

100 项与 AR x KLK3 x HDACs 相关的临床结果

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100 项与 AR x KLK3 x HDACs 相关的转化医学

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0 项与 AR x KLK3 x HDACs 相关的专利（医药）

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项与 AR x KLK3 x HDACs 相关的文献（医药）

2023-03-15·Cancers

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).

Article

作者: Tapadar, Subhasish ; Johnston, Alexis ; Gaul, David A. ; Tyagi, Ashish ; Oyelere, Adegboyega K. ; Saran, Uttara ; Wu, Bocheng ; Chandrasekaran, Balaji ; Damodaran, Chendil

BACKGROUNDEpigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC).METHODSSeveral rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo.RESULTSWhile screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR⁺ CRPC cells but not AR^- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR⁺ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues.CONCLUSIONThese results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.

2021-05-01·Cancer Letters1区 · 医学

Androgen deprivation-induced elevated nuclear SIRT1 promotes prostate tumor cell survival by reactivation of AR signaling

1区 · 医学

Article

作者: Huang, Shih-Bo ; Yang, X ; Lai, Z ; Ghosh, R ; Thapa, D ; Wang, Li-Ju ; Rivas, P ; Hussain, S S ; Chiu, Yu-Chiao ; Bedolla, R G ; Gaczynska, M E ; Kumar, A P ; Miyamoto, H ; Munoz, A R ; Chen, Y ; Shudde, C ; Osmulski, P ; Reddick, R L

The NAD⁺-dependent deacetylase, Sirtuin 1 (SIRT1) is involved in prostate cancer pathogenesis. However, the actual contribution is unclear as some reports propose a protective role while others suggest it is harmful. We provide evidence for a contextual role for SIRT1 in prostate cancer. Our data show that (i) mice orthotopically implanted with SIRT1-silenced LNCaP cells produced smaller tumors; (ii) SIRT1 suppression mimicked AR inhibitory effects in hormone responsive LNCaP cells; and (iii) caused significant reduction in gene signatures associated with E2F and MYC targets in AR-null PC-3 and E2F and mTORC1 signaling in castrate-resistant ARv7 positive 22Rv1 cells. Our findings further show increased nuclear SIRT1 (nSIRT1) protein under androgen-depleted relative to androgen-replete conditions in prostate cancer cell lines. Silencing SIRT1 resulted in decreased recruitment of AR to PSA enhancer selectively under androgen-deprivation conditions. Prostate cancer outcome data show that patients with higher levels of nSIRT1 progress to advanced disease relative to patients with low nSIRT1 levels. Collectively, we demonstrate that lowering SIRT1 levels potentially provides new avenues to effectively prevent prostate cancer recurrence.

2021-03-15·Aging3区 · 医学

Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment

3区 · 医学

Article

作者: Zheng, Hao ; Zhou, Maojun ; Li, Yubin ; Huang, Huichao ; Chen, Zhuchu ; Min, Xiaoli ; Xu, Guangyu ; Zhou, Wenqiang ; Chen, Yongheng ; Dai, Shuyan

Androgen receptor (AR) and histone deacetylase 6 (HDAC6) are important targets for cancer therapy. Given that both AR antagonists and HDAC6 inhibitors modulate AR signaling, a novel AR/HDAC6 dual inhibitor is investigated for its anticancer effects in castration-resistant prostate cancer (CRPC). Zeta55 inhibits nuclear translocation of AR and suppresses androgen-induced PSA and TMPRSS2 expression. Meanwhile, Zeta55 selectively inhibits HDAC6 activity, leading to AR degradation. Zeta55 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a CRPC xenograft model. These results provide preclinical proof of principle for Zeta55 as a promising therapeutic in prostate cancer treatment.