sulindac and Prostatic-Neoplasms

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Catechin; Female; Humans; Male; Neoplasms, Hormone-Dependent; Oncogenes; Prostatic Neoplasms; Sulindac

Prostate cancer represents the most common noncutaneous malignancy in men. With the widespread use of prostate-specific antigen screening, as many as one in six men in the USA will be diagnosed with prostate cancer. Significant healthcare resources are currently devoted to the treatment of this disease, specifically aimed at improving the side effects of successful treatment. Surgery or radiation therapy provides the best chance of cure from this disease. However, as many as 50% of patients treated with curative intent will develop a recurrence 10-15 years following treatment. Hormonal ablation via medical or surgical castration provides disease control, but is associated with significant hot flushes, loss of libido and impotence. Selective, apoptotic antineoplastic drugs, such as exisulind, may provide an alternative method to treating or preventing prostate cancer. This drug profile reviews the evidence for the use of exisulind in the treatment of prostate cancer.

Topics: Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Economics, Pharmaceutical; Humans; Male; Prostatic Neoplasms; Sulindac

Increased insight into the biology of prostate cancer and the emergence of new therapeutic strategies and chemotherapeutic agents has changed approaches in treating patients with advanced prostate cancer. After secondary hormonal manipulations, new approaches include: second-line hormonal therapy, chemotherapy, immunotherapy with granulocyte macrophage-colony stimulating factor (GM-CSF) therapy, dendritic cell therapy, gene vaccination therapy, inhibition and/or blockade of growth factor receptors or growth factor receptor pathways, inhibition of neo-angiogenesis and inhibition of invasion and metastases.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Cancer Vaccines; Diphosphonates; Genetic Therapy; Growth Inhibitors; Humans; Immunotherapy; Male; Prostatic Neoplasms; Sulindac; Vitamin D

Current treatments for androgen-independent prostate cancer have not shown a definitive increase in survival. Several novel drugs have made their way through preclinical testing into early clinical trials. Targets discussed in this review include apoptosis, antiangiogenesis, growth factor receptors or associated tyrosine kinases, and tumor-associated antigens targeted by vaccines. Research in this area includes testing combinations of previously studied chemotherapeutic agents as well as identifying and testing novel agents. It is these drugs, either alone or in combination, that are designed to target strategic pathways to improve survival and increase quality of life in prostate cancer patients. This review focuses on the novel agents being tested with chemotherapy in metastatic prostate cancer.

Topics: Androgens; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Cancer Vaccines; Humans; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Randomized Controlled Trials as Topic; Sulindac; Thalidomide

To evaluate the activity of exisulind against prostate cancer (CaP) in vivo through a prospective study of neoadjuvant exisulind in patients undergoing radical prostatectomy (RP). Exisulind and its analogs have been shown to induce apoptosis in vitro in many cancer cell lines, including CaP cell lines without affecting normal human cells.. Men with biopsy-proven, localized CaP (Gleason score ≥6) amenable to RP were offered enrollment into the trial. The treatment group (n = 44) was given oral exisulind (375-400 mg) daily for 4 weeks and then underwent RP. The control group underwent RP per routine (n = 49). The primary endpoint was change, from biopsy to prostatectomy specimens, in apoptosis biomarkers (bcl-2, Bax, par.-4, caspase 3, PTEN) between the 2 groups.. There were no significant effects of exisulind on biomarkers of cell death between biopsy specimen and posttreatment RP specimen. The drug was well tolerated and there were no drug-related serious adverse events or deaths.. Exisulind is a well-tolerated drug with minimal adverse events; however, we were unable to detect any significant differences in apoptotic biomarkers among those treated with neoadjuvant exisulind compared with controls at the dose and duration tested. Future studies should consider evaluating a higher dose or longer duration to better evaluate the role exisulind may play in the treatment of men with CaP.

Topics: Antineoplastic Agents; Apoptosis; Humans; Male; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Sulindac

To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors.. This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m(2) given on Day 1 of each 21-day cycle.. OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response.. The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mitoxantrone; Neoplasms; Prostatic Neoplasms; Sulindac; Testicular Neoplasms; Treatment Outcome; Urinary Bladder Neoplasms

Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug.. Eighty men with chemotherapy-naive HRPC were enrolled in a multicenter, cooperative group study. The treatment regimen consisted of oral estramustine (280 mg 3 times daily for 5 days), docetaxel 70 mg/m2, oral exisulind (250 mg twice daily), oral dexamethasone (8 mg twice daily for 3 days), and oral warfarin (2 mg daily).. Seventy-five eligible patients were treated with a median of 6 cycles of therapy. Fortyseven patients (62.7%; 95% CI, 50.7%-73.6%) had a > or = 50% decline in prostate-specific antigen levels. Forty-six patients had measurable disease with 6 partial responses (13%; 95% CI, 4.9%-26.3%). The main grade 3/4 toxicities were neutrophils (79%), fatigue (15%), and thrombosis/embolism (10%). The median time to first progression was 5.1 months (95% CI, 4.4-6.3 months) and the median survival time was 17.8 months (95% CI, 14.7-20.1 months).. The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Sulindac; Survival Analysis; Taxoids; Thromboembolism

In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind.. Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously.. All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added.. : Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Sulindac; Survival Analysis; Taxoids

To determine the safety and efficacy, in a dose-escalation study, of exisulind (an oral sulphone metabolite of sulindac thought to induce apoptosis in malignant cells by inhibiting cGMP-phosphodiesterase) combined with docetaxel in men with hormone-refractory prostate cancer (HRPC), as pre-clinical studies suggested activity against prostate cancer and synergy with cytotoxic agents.. Thirty-four patients with HRPC were treated with oral exisulind twice daily for 21-day cycles and intravenous docetaxel given for 1 h on the first day of each cycle. Three dose levels were assessed, combining exisulind 150 and 250 mg twice daily with docetaxel at 60 or 75 mg/m2. Toxicity was then evaluated using standard criteria.. The recommended phase II dose was determined to be exisulind 250 mg and docetaxel 60 mg/m2, with escalation to 75 mg/m2 after cycle 1, as tolerated. The most common grade 3-4 toxicities among all patients were neutropenia (56%), infection (24%) and hyperglycaemia (18%). Twelve of 32 evaluable patients (38%, 95% confidence interval, CI, 23-55%) had a decline in PSA by at least half. Only four of 17 evaluable patients (95% CI, 1-47%) treated at the phase II dose level had such a decline in PSA. The median (95% CI) overall survival of all patients was 16 (12.9-19.7) months and median progression-free survival 4.7 (2.7-5.2) months.. The combination of exisulind and docetaxel was tolerable in patients with HRPC. The PSA response rates do not suggest an improvement over historical data with single-agent docetaxel in this population.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Infusions, Intravenous; Male; Middle Aged; Prostatic Neoplasms; Sulindac; Taxoids

We evaluated the safety and efficacy of exisulind for delaying disease progression in men with increasing prostate specific antigen (PSA) after radical prostatectomy.. A total of 96 men with increasing PSA after radical prostatectomy were randomized to receive placebo (49) or 250 mg. exisulind twice daily (47) for 12 months. The primary efficacy parameter was the difference in change from baseline PSA between the placebo and exisulind groups. The PSA doubling time was also evaluated before and during study. A subgroup analysis classified patients based on the risk of developing metastatic disease.. Compared with placebo, exisulind significantly suppressed the increase in PSA in all patients (p = 0.017). The results were also statistically significant in men at high risk for metastasis (p = 0.0003) and those who could not be classified according to risk (p = 0.0009). In addition, median PSA doubling time was lengthened in high risk patients on exisulind (2.12 month increase) compared with those on placebo (3.37 month decrease, p = 0.048). Exisulind was well tolerated.. Exisulind inhibited the increase in PSA overall and prolonged PSA doubling time in high risk patients compared with placebo. These results suggest that Exisulind has the potential to extend the time from biochemical recurrence to the need for androgen deprivation therapy. Exisulind was well tolerated in this patient population. Our results support further study of Exisulind in the treatment of patients with prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Combined Modality Therapy; Double-Blind Method; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Complications; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Sulindac

Single-agent docetaxel has been shown to produce a significant decrease in prostate-specific antigen (PSA) levels among patients with hormone-refractory prostate cancer (HRPC). A recent study also showed that exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug sulindac, lengthens the median PSA doubling time in men who had increasing PSA levels after radical prostatectomy. Furthermore, exisulind has shown significant antineoplastic activity in prostate cancer cell lines in vitro and in nude mouse xenograft models. Because preclinical studies have suggested synergistic interactions between docetaxel and exisulind, a phase I/II clinical trial combining these agents has been initiated in patients with HRPC. The primary objective of this study is to determine PSA response and measurable disease response rate of the combination therapy; secondary objectives include toxicity assessment and determination of time to disease progression, duration of response, and overall survival. Accrual is ongoing.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Docetaxel; Humans; Male; Middle Aged; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Sulindac; Survival Analysis; Taxoids

Topics: Animals; Celecoxib; Cell Movement; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; HEK293 Cells; Humans; Inflammation; Interleukin-2; Male; Membrane Proteins; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Prostatic Neoplasms; Serine Endopeptidases; Sulindac; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac-NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1±4.1 and 12.1±3.2μM, respectively, coupled with observed nitric oxide release.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Molecular Structure; Nitric Oxide; Prostatic Neoplasms; Structure-Activity Relationship; Sulindac

Nonsteroidal anti-inflammatory drugs including sulindac are well documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX)-inhibitory activities cause severe gastrointestinal, renal, and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of nonsteroidal anti-inflammatory drugs and support the potential for the development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution called sulindac sulfide amide (SSA) was recently identified to be devoid of COX-inhibitory activity yet displays much more potent tumor cell growth-inhibitory activity in vitro compared with sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the transgenic adenocarcinoma of mouse prostate model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G(1) arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression through repressing cell proliferation in the transgenic adenocarcinoma of mouse prostate mice, whereas it did not significantly affect neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Cell Line, Tumor; Cell Proliferation; Chemoprevention; Disease Models, Animal; Growth Inhibitors; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Prostaglandin-Endoperoxide Synthases; Prostatic Neoplasms; Receptors, Androgen; Sulindac

Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Line, Tumor; Cell Nucleus; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Response Elements; RNA Interference; Signal Transduction; Sulindac

Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer.. We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays.. The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination.. In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Cyclin D1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; ErbB Receptors; Humans; Male; Methylnitrosourea; Prostatic Neoplasms; Pyrazoles; Rats; Rats, Wistar; Receptors, Androgen; Sulfonamides; Sulindac; Testosterone

Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.

Topics: Animals; Apoptosis; Body Weight; Cell Cycle; Cell Proliferation; Humans; Immunohistochemistry; Male; Mice; Neoplasm Transplantation; Paclitaxel; Pancreatic Neoplasms; Phosphorylation; Prostatic Neoplasms; Protein Kinase C; Retinoblastoma Protein; Sulindac; Tetradecanoylphorbol Acetate; Transplantation, Heterologous; Tretinoin; Tumor Cells, Cultured

The aim of our study was to explore the anti-tumoral potential of the Nitric Oxide-Donating Non-Steroidal Anti-Inflammatory Drugs (NO-NSAID) NCX1102 (nitrosulindac), on three human prostatic epithelial cell lines at varying degree of transformation (PNT1A, LNCaP, and PC3).. Cytotoxicity, anti-proliferative effects, cell-cycle alterations, morphological changes, and apoptosis were investigated after treatment with nitrosulindac in comparison to the native molecule sulindac. Involvement of the polyamine pathway in the action of nitrosulindac was also examined.. Nitrosulindac but not sulindac exerted a cytotoxic effect on all cell lines and an anti-proliferative effect on LNCaP and PC3 cells only. Nitrosulindac differentially altered the cell cycle, induced mitotic arrest and displayed a pro-apoptotic activity in all cell lines. Finally, the polyamine pathway does not seem to be involved in the mechanism of nitrosulindac action.. Our results demonstrate the anti-proliferative and proapoptotic activity of nitrosulindac on prostate cancer cell lines and suggest its potential interest for new strategies in the management of prostate cancer.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; Cell Survival; Epithelial Cells; Humans; Male; Nitric Oxide; Prostate; Prostatic Neoplasms; Sulindac

Epidemiologic studies have revealed a decreased risk of colon cancer among people who have regularly taken cyclooxygenase (COX)-2 inhibitors such as aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas the selective COX-2 inhibitor celecoxib and exisulind, a metabolic product of sulindac, have gained increasing attention as efficacious chemopreventive agents against colon and prostate cancer, not much is known about the underlying molecular targets and mechanisms. Moreover, the side effects of NSAIDs are a major obstacle for large-scale application to the prevention of cancer in humans; for example, in the United States in 1998, there were 16,550 deaths from NSAID-induced gastrointestinal complications. The toxicity associated with these compounds is raising concerns, and more needs to be known about their mode of action and molecular targets.. We used the transgenic mouse prostate (TRAMP) model, which exhibits similarities with human prostate cancer, including epithelial origin, progression from the PIN stage to adenocarcinoma, and metastasis by a transgene that is hormonally regulated by androgens. In addition to histologically analyzing the PIN lesions of the dorsolateral prostate from TRAMP mice, we delineated the molecular targets and mechanisms of celecoxib and exisulind against mouse PIN lesions. We performed Western blot analysis of the total protein lysate from the tissues of mouse PIN lesions to measure the level of expression of androgen receptor, vascular endothelial growth factor, nuclear factor-kappaB p65, BclII, AKT (total and phosphorylated Ser473), p53, cyclin-dependent kinase inhibitor p21WAF1/CIP1, p27, BAX, and caspase-3 to demonstrate the COX-2-independent mechanism involved in the inhibition of PIN lesions of the dorsolateral prostate by both celecoxib and exisulind.. We found for the first time that (a) both celecoxib and exisulind as dietary supplements induce strong inhibitory effects against prostate cancer at doses of 800 and 500 ppm, respectively, after 16 weeks; (b) the histologic analysis of the dorsolateral prostate after 2 weeks of treatment indicated a reduction of PIN lesions from 75% to 19% with celecoxib and to 16% with exisulind; (c) more importantly, those few PINs and adenocarcinomas in the groups treated with celecoxib or exisulind showed more apoptotic cells, lower levels of proliferating cell nuclear antigen, and a lower number of mitotic cells. To understand the molecular mechanisms involved in the inhibition of PIN lesions, first, we examined the expression of molecular targets involved in angiogenesis and inflammatory processes. It was clearly evident from Western blot analysis of the total protein lysate derived from the dorsolateral prostate tissues with PIN lesions that expression of androgen receptor, vascular endothelial growth factor, nuclear factor-kappaB p65, and BclII is down-regulated more effectively by celecoxib. Down-regulation of AKT protein (total and phosphorylated at Ser473) signaling by celecoxib clearly indicates an inhibition of the survival gene and the pathological process that could otherwise lead to adenocarcinoma.. Overall, the findings from this study clearly show the effectiveness of celecoxib and exisulind in reducing the PIN lesions by modulating a cascade of molecular targets involved in COX-2-dependent and -independent mechanisms. Whereas these agents are already in clinical trial or in use as chemopreventive agents, findings from this study demonstrate the difference in their mode of action, thus helping us to understand the side effects.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blotting, Western; Celecoxib; Dietary Supplements; Dinoprostone; Disease Models, Animal; Immunohistochemistry; Male; Mice; Mice, Transgenic; Models, Biological; Phosphorylation; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Pyrazoles; Sulfonamides; Sulindac; Time Factors; Transgenes

In recent studies, we found that sulindac sulfide (SS), exisulind, CP248, and CP461 induce growth inhibition and apoptosis in a series of human prostate cancer cell lines, irrespective of cyclooxygenase expression, p53 mutations, or bcl-2 overexpression. Exisulind also inhibited the growth of the androgen-dependent LNCaP human prostate cancer cell line when grown as a xenograft in nude mice. This study demonstrates that doses of these compounds that induce growth inhibition and apoptosis in LNCaP cells also cause decreased prostate-specific antigen (PSA) secretion and decreased cellular levels of PSA. These effects appear to be a result, at least in part, of inhibition of the androgen receptor (AR) signaling pathway because the treated cells also display decreases in the level of the AR protein and mRNA and inhibition of transcription of an AR promoter luciferase reporter in transient transfection assays. SS and exisulind were more effective in inhibiting the expression of PSA and the AR than CP248 or CP461, apparently because of differential effects of these compounds on specific transcription factors. These findings suggest that the growth inhibition by these compounds in human prostate cancer cells may be mediated, in part, by inhibition of AR signaling. Thus, these compounds may provide a novel approach to the prevention and treatment of human prostate cancer.

Topics: Antineoplastic Agents; Blotting, Northern; Cell Line, Tumor; Down-Regulation; Genes, Reporter; HSP70 Heat-Shock Proteins; Humans; Immunoblotting; Luciferases; Male; Mutation; Neoplasm Transplantation; Phosphodiesterase Inhibitors; Plasmids; Promoter Regions, Genetic; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Receptors, Androgen; RNA, Messenger; Signal Transduction; Sulindac; Time Factors; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53; Up-Regulation

Sulindac is the most extensively investigated clinically relevant chemopreventive nonsteroidal anti-inflammatory drug. Sulindac sulfide is one of the major metabolites of sulindac that is believed to mediate its antitumorigenic effects by inducing apoptosis. Recent evidence suggests that sulindac sulfide engages the mitochondrial pathway involving caspase 9 and Bax to mediate its apoptotic effects [Zhang et al., Science (Wash. DC), 290: 989-992, 2000]. In this report, we demonstrate that sulindac sulfide also engaged the membrane death receptor (DR) pathway to mediate apoptosis. Sulindac sulfide up-regulated DR5 and activated the proximal caspase 8 in various different colon and prostate cancer cell lines. Sulindac sulfide specifically up-regulated the DR5 levels but had no effect on the levels of other DRs including DR4, Fas, and tumor necrosis factor receptor 1. To further delineate the role of DR5 in sulindac sulfide-induced apoptosis, we used JCA-1 prostate cancer cells that are deficient in mounting a Fas and tumor necrosis factor receptor 1-dependent apoptotic response but are proficient in mediating DR5-dependent apoptosis. JCA-1 cells were stably transfected with dominant-negative Fas-associated death domain to block the flow of apoptotic signals originating from the endogenous DR5, and sulindac sulfide-induced apoptosis was investigated. Our results indicated that by blocking the DR5-dependent apoptotic pathway, dominant-negative Fas-associated death domain did indeed inhibit sulindac sulfide-induced apoptosis. Furthermore, exogenous tumor necrosis factor-related apoptosis-inducing ligand, the ligand for DR5, also potentiated sulindac sulfide-induced apoptosis in all of the cell lines tested, thereby further supporting the involvement of DR5 in sulindac sulfide-induced apoptosis. Thus, our results demonstrate that sulindac sulfide also engages the membrane DR pathway involving DR5 and proximal caspase 8 to induce apoptosis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Caspase 8; Caspase 9; Caspases; Colonic Neoplasms; Enzyme Activation; HT29 Cells; Humans; Male; Prostatic Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; RNA, Messenger; Sulindac; Tumor Cells, Cultured; Up-Regulation

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antineoplastic Agents; Apoptosis; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Humans; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms; Sulindac

Topics: Adult; Aged; Androgen Antagonists; Antineoplastic Agents; Disease Progression; Drug Administration Schedule; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Sulindac; Time Factors

Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model.. Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay.. Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P<0.0001) but no change in the number of BrdU positive cells.. This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Division; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Prostatic Neoplasms; Sulindac

We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.

Topics: Androgens; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Cell Division; Cyclooxygenase Inhibitors; Drug Screening Assays, Antitumor; Humans; Male; Prostaglandin-Endoperoxide Synthases; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulindac; Tumor Cells, Cultured