curcumin and Prostatic-Neoplasms--Castration-Resistant

Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients.. A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm).. Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47).. Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Curcumin; Disease Progression; Docetaxel; Double-Blind Method; Drug Administration Schedule; Early Termination of Clinical Trials; Humans; Male; Medical Futility; Medication Adherence; Middle Aged; Placebos; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life

Favorable phase I results justified this pilot phase II study to assess the efficacy of docetaxel/curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC).. Thirty patients with progressing CRPC and a rising prostate-specific antigen (PSA) received docetaxel/prednisone in standard conditions for 6 cycles in combination with per os curcumin, 6,000 mg/day (day -4 to day +2 of docetaxel). The co-primary endpoint was the overall response rate determined by PSA and target assessments. An ancillary study assessed the seric values of chromogranin A (CgA) and neuron-specific enolase (NSE).. Twenty-six patients received the scheduled treatment, 2 progressed and 2 died before the end of treatment. A PSA response was observed in 59% of patients (14% of PSA normalization) and achieved within the first three cycles for 88% of responders. Partial response was reached for 40% of evaluable patients. The regimen was well tolerated, and no adverse event was attributed to curcumin. Twenty patients were 100% curcumin compliant. The PSA level and objective response rate were not correlated with the serum values of CgA and NSE.. This study produced additional data on curcumin as a treatment for cancer, with a high response rate, good tolerability and patient acceptability, justifying the interest to conduct a randomized trial.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromogranin A; Curcumin; Docetaxel; Geriatric Assessment; Humans; Male; Medication Adherence; Middle Aged; Phosphopyruvate Hydratase; Pilot Projects; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids; Treatment Outcome

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

Many prostate cancer patients develop resistance to treatment called castration-resistant prostate cancer (CRPC) which is the major cause of recurrence and death. In the present study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anticancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti-metastasis properties and found that 2,6-bis-(4-hydroxy-3-methoxy-benzylidene)-cyclohexanone (2A) and 2,6-bis-(3,4-dihydroxy-benzylidene)-cyclohexanone (2F) showed higher anti-invasion properties against CRPC cells than curcumin. Analog 2A inhibited both MMP-2 and MMP-9 secretions and activities, whereas analog 2F reduced only MMP activities. These findings suggest that the compounds may inhibit CRPC cell metastasis by decreased extracellular matrix degradation. Analog 2A, the most potent analog, was then subjected to an in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 minutes after i.p. injections. Analog 2A and curcumin (30 mg/kg bodyweight) showed a similar ability to reduce tumor area in lungs of mice that were i.v. injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 cells than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 cells growth by induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with downregulation of cell proliferation and angiogenesis in PLS10-bearing mice. Taken together, we could summarize that analog 2A showed promising activities in inhibiting CRPC progression both in vitro and in vivo.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclohexanones; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Recurrence, Local; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; Xenograft Model Antitumor Assays

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

Prostate cancer is initially sensitive to hormone therapy; however, over time the majority of patients progress to a hormone-insensitive form classified as castration-resistant prostate cancer (CRPC). CRPC is highly metastatic and patients have a poor prognosis. Thus, new drugs for the treatment of this disease are required. In this study, we therefore examined the cytotoxic effects and anticancer mechanism(s) of action of second generation curcumin analogs towards CRPC cells. For this purpose, PC3 and DU145 cells were treated with a series of curcumin analogs at 0-10 µM for 72 h and cytotoxicity was determined by the sulforhodamine B (SRB) assay. Two compounds, 1-isopropyl-3,5-bis(pyridin-3-ylmethylene)-4-piperidone (RL118) and 1-methyl-3,5-[(6-methoxynaphthalen-2-yl)methylene]-4-piperidone (RL121), were found to have the most potent cytotoxic effect with EC50 values of 0.50 and 0.58 µM in the PC3 cells and EC50 values of 0.76 and 0.69 µM in the DU145 cells, respectively. Thus, further experiments were performed focusing on these two compounds. Flow cytometry was performed to determine their effects on the cell cycle and apoptosis. Both analogs increased the number of cells in the G2/M phase of the cell cycle and induced apoptosis. Specifically, in the PC3 cells, RL121 increased the number of cells in the G2/M phase by 86% compared to the control, while RL118 increased the number of cells in the G2/M phase by 42% compared to the control after 24 h. Moreover, both RL118 and RL121 induced the apoptosis of both cell lines. In the DU145 cells, a 38-fold increase in the number of apoptotic cells was elicited by RL118 and a 78-fold increase by RL121 compared to the control. Furthermore, the effects of both analogs on the expression of key proteins involved in cell proliferation were also determined by western blot analysis. The results revealed that both analogs inhibited the expression of nuclear factor (NF)-κB (p65/RelA), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), p-4E-BP1, mammalian target of rapamycin (mTOR), p-mTOR, AKT and p-AKT. Thus, the findings of this study provide evidence that RL118 and RL121 have potent anticancer activity against CPRC cells, and both analogs warrant further investigation in vivo.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Male; Piperidones; Prostatic Neoplasms, Castration-Resistant; Pyridines

Androgen deprivation therapy remains the principal treatment for patients with advanced prostate cancer, though, most patients will eventually develop hormone-refractory prostate cancer (HRPC). Androgen ablation mediated maspin-induction has been identified in cancer patients. However, the role of maspin on the anticancer activity of curcumin derived from turmeric (Curcuma longa) in HRPC cells has not been elucidated.. The anticancer action of curcumin in hormone-independent prostate cancer cells (DU145, and PC-3) was determined by measures of cell survival rate. The cause of maspin silencing on the anti-tumor abilities of curcumin in PC-3 cells was evaluated by measures of cell survival rate, cell-cycle distribution, and apoptosis signaling analysis.. Our present study showed that PC-3 cells (with higher maspin expression) were more sensitive than DU145 cells to curcumin treatment (with lower maspin expression). RNA interference-mediated maspin silencing reduced curcumin sensitivity of PC-3 cells, as evidenced by reduced apoptotic cell death. After exposure to curcumin, maspin-knockdown cells showed lower expression levels of pro-apoptotic proteins, Bad and Bax, as compared with control cells.. Maspin can enhance the sensitivity of HRPC cells to curcumin treatment.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Down-Regulation; Gene Knockdown Techniques; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Serpins

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

Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC) cells through its iron-chelating properties.. CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC). Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II) using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) were examined by Western blot.. Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA]) synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin.. Together, our results indicate that curcumin induces apoptosis and protective autophagy in CRPC cells, which are at least partially dependent on its iron-chelating properties.

Topics: Apoptosis; Autophagy; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Humans; Iron Chelating Agents; Male; Prostatic Neoplasms, Castration-Resistant; Structure-Activity Relationship; Tumor Cells, Cultured

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

There is a critical need for therapeutic agents that can target the amino-terminal domain (NTD) of androgen receptor (AR) for the treatment of castration-resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen-regulated genes whose expression was significantly (p ≤ 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgen-regulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC.

Topics: Animals; Cell Proliferation; Curcumin; Gene Expression; Humans; Male; Mice; Mice, Nude; NIH 3T3 Cells; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Random Allocation; Receptors, Androgen; Xenograft Model Antitumor Assays

Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3-9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX's (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections indicated decreased Ki-67 staining and increased TUNEL intensity in mice exposed to the 3-drug combination. Therefore, subverting ER-stress towards apoptosis using adjuvant therapy with NFR and CUR can chemosensitize the CRPC cells to DTX therapy.

Topics: Animals; Apoptosis; Cell Line, Tumor; Curcumin; Docetaxel; Endoplasmic Reticulum Stress; Epithelial Cells; Humans; Male; Mice; Mice, Nude; Nelfinavir; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Taxoids; Thapsigargin

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