Bruceantin, an amoebicidal anti-malarial agent from a plant, Brucea antidysenterica identified as potential drug for castrate resistant PCa

[Graham49]

Full paper available on Google Scholar

Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer

Theranostics. 2021:11(2):958-973

Sue Jin Moon, Byong Chang Jeong, [...], and Jeong Hoon Kim

Abstract

Rationale: Aberrant androgen receptor (AR) signaling via full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities.

Methods: Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses.

Results: We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC.

Conclusion: Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.

[cesces]

There is a lot of interesting stuff out there.

What we really need to do is develop a better clinical trials pipeline to get these things approved for access.

This is particularly important for medications that have been approved for alternative indications.

[tango65]

Link to the full article:

thno.org/v11p0958.pdf

This article is an in vitro cell culture study. It does have anti cancer properties in cell cultures.

Bruceantin failed phase I-II clinical trials designed to treat leukemias and lymphomas.

pubmed.ncbi.nlm.nih.gov/149...

[Graham49]

This is what Medchemexpress says about Bruceantin

Bruceantin(NSC165563) is first isolated from Brucea antidysenterica, a tree used in Ethiopia for the treatment of cancer, and activity was observed against B16 melanoma, colon 38, and L1210 and P388 leukemia in mice. IC50 value: Target: anticancer Cell differentiation was induced and c-MYC was down-regulated, suggesting a mechanistic correlation between c-MYC down-regulation and induction of cell differentiation or cell death. Treatment of HL-60 and RPMI 8226 cell lines induced apoptosis, and this involved the caspase and mitochondrial pathways. Moreover, an in vivo study using RPMI 8226 human-SCID xenografts demonstrated that bruceantin induced regression in early as well as advanced tumors, and these significant antitumor responses were facilitated in the absence of overt toxicity.

[j-o-h-n]

Grow hair?

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 01/06/2021 6:54 PM EST