Efficacy of a known anti-malarial drug for castration-resistant prostate cancer
By Dr Bushra Ateeq, Intermediate Fellow
Majority of prostate cancer patients with the organ confined or localized disease undergo hormonal therapies targeting various nodes of the androgen receptor signalling pathway, such as androgen deprivation therapy (ADT), involving either surgical or chemical castration. Although, ADT remains the mainstay for the treatment of metastatic prostate cancer, most of these patients invariably develop resistance, leading to an aggressive stage, termed “metastatic castration-resistant prostate cancer” (mCRPC). In this study, we have employed “drug repurposing or repositioning” strategy to address this problem. We have shown that, Artesunate, which is an U.S. Food and Drug Administration (FDA) - and World Health Organization (WHO) - approved anti-malarial drug derived from sweet wormwood (Artemisia annua), could be used to restore the sensitivity of the mCRPC condition to anti-androgens or ADT. This study for the first time provides a compelling pre-clinical rationale that Artesunate in combination with Bicalutamide, an androgen receptor antagonist (anti-androgens) reduces oncogenic properties of the castrate-resistant prostate cancer cells. Moreover, mechanistically the drug combination induces oxidative stress, cell death and inhibits NF-κB signalling, which leads to degradation of androgen receptor, subsequently sensitizes castrate-resistant prostate cancer cells to anti-androgen therapy and revokes their oncogenic potential. Most importantly, this combinatorial therapy demonstrates very promising regression (>95% reduction) in tumor burden and decreased metastases to lungs and bones in CRPC tumors bearing mice. Thus, the current study strongly indicates an immediate requirement for conducting the well-planned clinical trials using Artesunate in combination with anti-androgens for mCRPC patients.
Figure: Schema showing mechanistic details of treatment with artesunate alone or in combination with anti-androgen mediated restoration of sensitivity to androgen receptor antagonists in castration resistant prostate cancer.
Targeting NF-kappa B signaling by Artesunate restores sensitivity of castrate-resistant prostate cancer cells to anti-androgens. Nunes JJ#, Pandey SK#, Yadav A#, Goel S, Ateeq B*. Neoplasia. Volume 19, Issue 4, April 2017, 333-345. doi: 10.1016/j.neo.2017.02.002.
Banner Image Credit Mateus Crespo, The Institute of Cancer Research, Wellcome Images
Castration resistant prostate cancer, human tissue
Multicolour immunofluorescence staining of human tissue from a castration resistant prostate cancer patient. The prostate cancer cells (bottom left and top of image) express both androgen receptor (red) and intermediate filament proteins (yellow). They extend into the bladder (yellow only; middle left to bottom centre of image) and are surrounded by white blood cells (cyan/light blue) that are infiltrating into the area. Cell nuclei (dark blue) are also visible. In men with castration-resistant disease, the cancer is able to continue growing despite lowering hormone androgen levels either by surgically removing the testicles or with medication that stop the testicles from making androgens or that block their effect on the body. Width of image is approximately 690 micrometres.