1-7-bis(4-hydroxy-3-methoxyphenyl)-1-4-6-heptatrien-3-one and Prostatic-Neoplasms--Castration-Resistant

Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells.. By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism.. We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells.. We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be considered as a new therapeutic option for the prevention or treatment of docetaxel resistance.

Topics: Androgen Receptor Antagonists; Antibodies, Monoclonal; Antineoplastic Agents; Cell Line, Tumor; Coculture Techniques; Combined Modality Therapy; Curcumin; Docetaxel; HEK293 Cells; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Lectins, C-Type; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Receptors, Cell Surface; Up-Regulation

ASC-J9

Topics: Animals; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Approval; HEK293 Cells; Humans; Male; Mice, Nude; Prostatic Neoplasms, Castration-Resistant; Proteolysis; Receptors, Androgen; Solutions; United States; United States Food and Drug Administration; Xenograft Model Antitumor Assays

While androgen-deprivation-therapy with the recently developed antiandrogen enzalutamide (Enz) shows promising therapeutic benefits in men with metastatic castration-resistant prostate cancer (PCa), many patients develop resistance to Enz, which may involve the induction of the androgen receptor (AR) splicing variant 7 (AR-v7).. Our aim is to identify the mechanisms responsible for AR-v7 production and to develop novel preclinical approaches to suppress the Enz-resistant (EnzR) PCa.. We established EnzR-PCa cell lines and examined the long noncoding RNA Malat1 (Malat1) function in conferring Enz resistance. We also examined the in vivo effects of Malat1 short interfering RNA and the AR-v7 degradation enhancer, ASC-J9. Enz resistance and expression of Malat1 and AR-v7. All statistical comparisons were analyzed with a t-test or one way analysis of variance followed by t-test.. We demonstrated that Malat1 is indispensable for Enz-induced AR-v7 production in VCaP and EnzR-C4-2 cells. We observed increased AR-v7 and Malat1 expression in our established EnzR-PCa cell lines and in some PCa patients who received Enz treatment. Targeting the Malat1/AR-v7 axis resulted in altering the PCa resistance to androgen deprivation therapy with Enz. The limitation of this study includes the small sample size from the same human patients before and after receiving Enz treatment.. Targeting the Malat1/AR-v7 axis via Malat1-short interfering RNA or AR-v7 degradation enhancer ASC-J9. Androgen deprivation therapy-enzalutamide treatment may not be the best choice for prostate cancer patients who have higher expression of the Malat1/androgen receptor splicing variant 7 axis, and new therapies using Malat1-short interfering RNA or ASC-J9

Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Phytogenic; Benzamides; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Nude; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Proteolysis; Receptors, Androgen; RNA Interference; RNA, Long Noncoding; RNAi Therapeutics; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Benzamides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Humans; Male; Mutation; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Proteolysis; Receptors, Androgen; Signal Transduction; Time Factors; Transcription, Genetic; Transfection

Androgen deprivation therapy has been the standard treatment for the patients with advanced prostate cancer. Androgen deprivation therapy initially suppresses the growth of prostate cancer. However, most patients eventually progress to castration-resistant prostate cancer. Novel drugs, including enzalutamide and abiraterone acetate, are recently able to be used for the patients with castration-resistant prostate cancer. Even so, the therapeutic options for castration-resistant prostate cancer are not enough. Interestingly, androgen receptor degradation enhancer ASC-J9 is reported to degrade the androgen receptor, resulting in the suppression of the growth in castration-resistant prostate cancer cells. In this chapter, ASC-J9 for prostate cancer is reviewed.

Topics: Androgen Antagonists; Animals; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen