curcumin and hydroxyflutamide

The androgen receptor (AR) is a ligand-activated transcription factor that is expressed in primary and metastatic prostate cancers. There are advances in endocrine therapy for prostate cancer that are based on improved understanding of AR function.. PubMed has been used to include most important publications on targeting the AR in prostate cancer. AR expression may be downregulated by agents used for chemoprevention of prostate cancer or, in models of advanced prostate cancer, by antisense oligonucleotides. New drugs that inhibit the steroidogenic enzyme CYP17A1 (abiraterone acetate) or diminish nuclear translocation of the AR (enzalutamide) have been shown to improve patients' survival in prostate cancer. However, it is clear that there is a development of resistance to these novel therapies. They may include increased expression of truncated, constitutively active AR or activation of the signaling pathway of signal transducers and activators of transcription.. Although introduction of novel drugs have improved patients' survival, there is a need to investigate the mechanisms of resistance further. The role of truncated AR and compensatory activation of signaling pathways as well as the development of scientifically justified combination therapies seems to be issues of a high priority.

Topics: Androgen Antagonists; Anilides; Antibodies, Neutralizing; Anticarcinogenic Agents; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Curcumin; Flutamide; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Male; Molecular Targeted Therapy; Nitriles; Oligonucleotides, Antisense; Phenylthiohydantoin; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Tosyl Compounds

Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5β1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress.

Topics: Androgen Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Disease Progression; Drug Synergism; Female; Flutamide; Gene Expression; Humans; Integrin alpha5beta1; Interleukin-6; Macrophages; Mice; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome; Urinary Bladder Neoplasms