tretinoin and Prostatic-Neoplasms--Castration-Resistant

Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Male; Mice, Inbred NOD; Mice, SCID; Naphthoquinones; NIMA-Interacting Peptidylprolyl Isomerase; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; Protein Domains; Receptors, Androgen; Signal Transduction; Tretinoin; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Alternative Splicing; Animals; Antineoplastic Agents; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Protein Serine-Threonine Kinases; Receptors, Androgen; RNA Interference; Signal Transduction; Tretinoin; Xenograft Model Antitumor Assays

Technology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa.. We established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs.. CRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling.. The phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language.. We generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids.. Comprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC.. We describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.

Topics: Aniline Compounds; Antineoplastic Agents; Bexarotene; Cellular Reprogramming Techniques; Drug Screening Assays, Antitumor; High-Throughput Screening Assays; Humans; Kallikreins; Keratin-18; Keratin-5; Male; Organoplatinum Compounds; Oxaliplatin; Precision Medicine; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quinacrine; Receptors, Androgen; Sulfonamides; Tetrahydronaphthalenes; Tretinoin; Tumor Cells, Cultured

Androgen receptor (AR) and MNK activated eIF4E signaling promotes the development and progression of prostate cancer (PCa). In this study, we report that our Novel Retinamides (NRs) target both AR signaling and eIF4E translation in androgen sensitive and castration resistant PCa cells via enhancing AR and MNK degradation through ubiquitin-proteasome pathway. Dual blockade of AR and MNK initiated eIF4E activation by NRs in turn induced cell cycle arrest, apoptosis, and inhibited cell proliferation. NRs also inhibited cell migration and invasion in metastatic cells. Importantly, the inhibitory effects of NRs on AR signaling, eIF4E translation initiation and subsequent oncogenic program were more potent than that observed with clinically relevant retinoids, established MNK inhibitors, and the FDA approved PCa drugs. Our findings provide the first preclinical evidence that simultaneous inhibition of AR and eIF4E activation is a novel and efficacious therapeutic approach for PCa, and that NRs hold significant promise for treatment of advanced prostate cancer.

Topics: Androgen Antagonists; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptors, Androgen; RNA Interference; Signal Transduction; Time Factors; Transfection; Tretinoin

All-trans retinoic acid (ATRA), the active form of vitamin A, plays an important role in the growth arrest of numerous types of cancer cells. It has been indicated that cyclin-dependent kinase 5 (Cdk5) activity can be affected by ATRA treatment. Our previous results demonstrate the involvement of Cdk5 in the fate of prostate cancer cells. The purpose of this study is to examine whether Cdk5 is involved in ATRA-induced growth arrest of the castration-resistant cancer cell line DU145 through up-regulating Cdk inhibitor protein, p27.. DU145 cells were treated with ATRA, and cell proliferation, protein expression, and protein localization of Cdk5/p27 were examined. Cell proliferation and cell cycle distribution were also determined under Cdk5 inhibition induced by inhibitor or knockdown.. ATRA treatment inhibited DU145 cell proliferation and significantly increased p27 expression through Cdk5 up-regulation. Immunocytochemical data showed that a Cdk5 inhibitor reduced ATRA-triggered nuclear distribution of p27 in DU145 cells. The proliferation inhibition and G1 phase accumulation of DU145 cells were significantly increased by ATRA treatment, whereas Cdk5 inhibitor and siRNA could reverse these effects.. Our results demonstrate that ATRA induced growth inhibition in castration-resistant prostate cancer cells through activating Cdk5 and p27. We hope this finding will increase the knowledge of prostate cancer treatment and can be applied in patients' nutritional control in the future.

Topics: Antineoplastic Agents; Blotting, Western; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Male; Microscopy, Confocal; Prostatic Neoplasms, Castration-Resistant; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tretinoin