Quadruple-negative breast cancer: novel implications for a new disease.

Based on the androgen receptor (AR) expression, triple-negative breast cancer (TNBC) can be subdivided into AR-positive TNBC and AR-negative TNBC, also known as quadruple-negative breast cancer (QNBC). QNBC characterization and treatment is fraught with many challenges. In QNBC, there is a greater paucity of prognostic biomarkers and therapeutic targets than AR-positive TNBC. Although the prognostic role of AR in TNBC remains controversial, many studies revealed that a lack of AR expression confers a more aggressive disease course. Literature characterizing QNBC tumor biology and uncovering novel biomarkers for improved management of the disease remains scarce. In this comprehensive review, we summarize the current QNBC landscape and propose avenues for future research, suggesting potential biomarkers and therapeutic strategies that warrant investigation.

A critical update on the strategies towards modulators targeting androgen receptors.

Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. In this review, we discussed some new strategies for targeting androgen receptors through degradation pathways as potential treatments for prostate cancer.

Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17ß-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists.

Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17ß-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.

AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer.

BACKGROUND: Prostate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10-17% CRPC patients. The detailed mechanisms remain unclear.. METHODS: The expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting. RESULTS: The protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/AKT signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists. CONCLUSIONS: TOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.

Synthesis, biological evaluation, and molecular docking of novel hydroxyzine derivatives as potential AR antagonists.

Prostate cancer (PCa) is a malignant tumor with a higher mortality rate in the male reproductive system. In this study, the hydroxyazine derivatives were synthesized with different structure from traditional anti-prostate cancer drugs. In the evaluation of in vitro cytotoxicity and antagonistic activity of PC-3, LNCaP, DU145 and androgen receptor, it was found that the mono-substituted derivatives on the phenyl group (4, 6, 7, and 9) displayed strong cytotoxic activities, and compounds 11-16 showed relatively strong antagonistic potency against AR (Inhibition% >55). Docking analysis showed that compounds 11 and 12 mainly bind to AR receptor through hydrogen bonds and hydrophobic bonds, and the structure-activity relationship was discussed based on activity data. These results suggested that these compounds may have instructive implications for drug structural modification in prostate cancer.

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer.

Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2-3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR­dependent and contribute to PCa drug resistance will be discussed.

The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH.

Based on the SAR of both α1-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C6min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α1-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.

Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications.

Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient's response to androgen ablation therapy is variable, and 20-30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.

Therapeutic targeting of the androgen receptor (AR) and AR variants in prostate cancer.

Prostate cancer (PCa) accounted for over 300 000 deaths world-wide in 2018. Most of the PCa deaths occurred due to the aggressive castration-resistant PCa (CRPC). Since the androgen receptor (AR) and its ligands contribute to the continued growth of androgen-dependent PCa (ADPCa) and CRPC, AR has become a well-characterized and pivotal therapeutic-target. Although AR signaling was identified as therapeutic-target in PCa over five-decades ago, there remains several practical issues such as lack of antagonist-bound AR crystal structure, stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction, unfavorable large-molecule accommodation of the ligand-binding domain (LBD), and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs. This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future AR-targeted drug development of potent next-generation molecules. The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.

Design and synthesis of novel steroidal imidazoles as dual inhibitors of AR/CYP17 for the treatment of prostate cancer.

Both AR and CYP17 are important targets for blocking androgen signaling, and it has been accepted that multifunctional drugs have a low risk of drug resistance in the treatment of cancer. Thus, herein a series of steroidal imidazoles were designed, synthesized and evaluated as dual AR/CYP17 ligands. Several compounds displayed good biological profiles in both enzymatic and cellular assays. SAR studies showed that introducing oximino at the C-3 position of steroidal scaffold is beneficial to the enhancement of AR antagonistic activity. Among these compounds, the most potent compound 13a exhibited the best AR inhibition (IC50 = 0.5 µM) that was 27-fold increase compared with the hit compound 5 as well as comparable CYP17 inhibition (IC50 = 11 µM). Additionally, 13a displayed promising anti-proliferative effects on LNCap cell lines with the IC50 value of 23 µM which was superior to positive control Flutamide (IC50 = 28 µM). Furthermore, the docking results of 13a revealed that the oxygen atom at the position of C-3 connected to the heme of CYP17, which may be helpful for its satisfactory dual-target inhibition. In summary, this study provides an efficient strategy for multi-targeting drug discovery in the treatment of prostate cancer.

Non-Genomic Actions of the Androgen Receptor in Prostate Cancer.

Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein-protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.

Bisphenol-A promotes antiproliferative effects during neonatal prostate development in male and female gerbils.

The aim of this study was to evaluate the development of male and female neonatal gerbil prostate under normal conditions and exposed to bisphenol-A (BPA). Normal postnatal development of the female gerbil prostate occurs earlier than and is morphologically distinct from that occurring in males. In BPA-exposed PND8 gerbils, we have not observed evidence of alterations in the ductal branching in either gender. However, the exposure to BPA alters the immunolabeling pattern of AR, ERα, and PCNA. In males, the exposure to high dosages of BPA resulted in a decrease in the proliferative status of the developing ventral prostate. In females, both high and low dosages were sufficient to decrease the proliferation of paraurethral buds in the branching process by more than 50%. Therefore, the obtained data indicate that BPA promotes antiproliferative effects during the neonatal development of the gerbil prostate, with more sensitivity to this endocrine disruptor in females.

3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a novel adenosine receptor antagonist with A(2A)-mediated neuroprotective effects.

In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.