Therapy For Hormone-refractory Prostate Cancer Research Articles

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Background/Aims: Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide. Currently available therapies for hormone-refractory PCa are only marginally effective. Plumbagin (PLB), a natural naphthoquinone isolated from the traditional folk medicine Plumbago zeylanica, is known to selectively kill tumor cells. Nevertheless, antitumor mechanisms initiated by PLB in cancer cells have not been fully defined. Methods: MTT assay was used to evaluate the effect of PLB on the viability of cancer cells. Cell apoptosis and reactive oxygen species (ROS) production were determined by flow cytometry. Protein expression was detected by western blotting. In vivo anti-tumor effect was measured by using tumor xenoqraft model in nude mice. Results: In the present study, we found that PLB decreases cancer cell growth and induces apoptosis in DU145 and PC-3 cells. In addition, by increasing intracellular ROS levels, PLB induced a lethal endoplasmic reticulum stress response in PCa cells. Importantly, blockage of ROS production significantly reversed PLB-induced ER stress activation and cell apoptosis. In vivo, we found that PLB inhibits the growth of PCa xenografts without exhibiting toxicity Treatment of mice bearing human PCa xenografts with PLB was also associated with induction of ER stress activation. Conclusion: Inducing ER stress by PLB thus discloses a previously unrecognized mechanism underlying the biological activity of PLB and provides an in-depth insight into the action of PLB in the treatment of hormone-refractory PCa.

MP55-07 FLAVONOIDS ENHANCE TRAIL SENSITIVITY IN PROSTATE CANCER CELLS BY TARGETING ADENINE NUCLEOTIDE TRANSLOCASE-2

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2015MP55-07 FLAVONOIDS ENHANCE TRAIL SENSITIVITY IN PROSTATE CANCER CELLS BY TARGETING ADENINE NUCLEOTIDE TRANSLOCASE-2 Masakatsu Oishi, Takashi Ueda, Terukazu Nakamura, Yoshio Naya, Fumiya Hongo, Kazumi Kamoi, Koji Okihara, and Tsuneharu Miki Masakatsu OishiMasakatsu Oishi More articles by this author , Takashi UedaTakashi Ueda More articles by this author , Terukazu NakamuraTerukazu Nakamura More articles by this author , Yoshio NayaYoshio Naya More articles by this author , Fumiya HongoFumiya Hongo More articles by this author , Kazumi KamoiKazumi Kamoi More articles by this author , Koji OkiharaKoji Okihara More articles by this author , and Tsuneharu MikiTsuneharu Miki More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2050AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been under clinical trials, whereas various kinds of malignant tumors have resistance to TRAIL. It has been shown that several anticancer agents and flavonoids (apigenin, quercetin etc.) overcome resistance to TRAIL by upregulating death receptor 5 (DR5) in malignant tumor cells. However, the mechanisms by which these compounds induce DR5 expression remain unknown. On the other hand, although docetaxel plus prednisone is effective in hormone-refractory prostate cancer, the outcome of this treatment is still insufficient. Therefore, new strategies are needed to treat this cancer. Thus we investigated the mechanism in a hormone-refractory prostate cancer cell line DU145. METHODS To elucidate the mechanisms by which flavonoids induce DR5 expression in DU145 cells, we explored the proteins binding to flavonoids using FG beads with epoxy linkers. We fixed genistein, which enhances TRAIL sensitivity without upregulating DR5, apigenin, and quercetin onto these beads (Figure 1A). The binding proteins of apigenin, quercetin, and genistein were purified from the DU145 whole cell extracts and were identified by MALDI-TOF MS analysis. Then, function of binding proteins was analized. RESULTS Comparing the binding proteins, we discovered that ANT2 was a target of apigenin and quercetin, but not genistein in DU145 cells (Figure 1B). Similarly to treatment of apigenin and quercetin, knockdown of ANT2 enhanced TRAIL-induced apoptosis by upregulating DR5 expression. Moreover, silencing of ANT2 attenuated the enhancement of TRAIL-induced apoptosis by apigenin or quercetin. CONCLUSIONS These results suggest that flavonoids upregulate DR5 and enhance TRAIL-induced apoptosis in hormone-refractory prostate cancer cells by binding and inhibiting ANT2 (Figure 1C). We propose that ANT2 inhibitors may contribute to TRAIL therapy in hormone-refractory prostate cancer. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e675 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masakatsu Oishi More articles by this author Takashi Ueda More articles by this author Terukazu Nakamura More articles by this author Yoshio Naya More articles by this author Fumiya Hongo More articles by this author Kazumi Kamoi More articles by this author Koji Okihara More articles by this author Tsuneharu Miki More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Targeted prodrug approaches for hormone refractory prostate cancer.

Due to the propensity of relapse and resistance with prolonged androgen deprivation therapy (ADT), there is a growing interest in developing non-hormonal therapeutic approaches as alternative treatment modalities for hormone refractory prostate cancer (HRPC). Although the standard treatment for HRPC consists of a combination of ADT with taxanes and anthracyclines, the clinical use of chemotherapeutics is limited by systemic toxicity stemming from nondiscriminatory drug exposure to normal tissues. In order to improve the tumor selectivity of chemotherapeutics, various targeted prodrug approaches have been explored. Antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) strategies leverage tumor-specific antigens and transcription factors for the specific delivery of cytotoxic anticancer agents using various prodrug-activating enzymes. In prostate cancer, overexpression of tumor-specific proteases such as prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) is being exploited for selective activation of anticancer prodrugs designed to be activated through proteolysis by these prostate cancer-specific enzymes. PSMA- and PSA-activated prodrugs typically comprise an engineered high-specificity protease peptide substrate coupled to a potent cytotoxic agent via a linker for rapid release of cytotoxic species in the vicinity of prostate cancer cells following proteolytic cleavage. Over the past two decades, various such prodrugs have been developed and they were effective at inhibiting prostate tumor growth in rodent models; several of these prodrug approaches have been advanced to clinical trials and may be developed into effective therapies for HRPC.

Abstract 242: Anti-obesity drugorlistat enhances sensitivity toTRAIL by two different pathways inhormone-refractory prostate cancer cells

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as one of the expected cancer therapeutics. However, since hormone-refractory prostate cancer (HRPC) cells are sometimes resistant to TRAIL, we need to develop a novel strategy to overcome. We demonstrated that the anti-obesity drug orlistat enhances the sensitivity to TRAIL in HRPC cells. The combination of orlistat and TRAIL remarkably induced apoptosis in DU145 and PC3 cells. Orlistat induced the expression of DR5, which is one of the TRAIL receptors. The suppression of DR5 with siRNA reduced the enhanced apoptosis, suggesting that the enhanced apoptosis was at least partially due to the up-regulation of DR5. Although the up-regulation of DR5 at both mRNA and protein levels by orlistat was observed in both cell lines, the activation of the DR5 promoter in DU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover, orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminished the sensitivity to TRAIL through the suppression of the CHOP and DR5 expressions in both cell lines. These results suggest that there are two different pathways of up-regulation of DR5 by orlistat, which are ROS-CHOP pathway and ROS-direct pathway. In conclusion, orlistat enhances the sensitivity to TRAIL in the ROS mediated pathways in prostate cancer cells. We believe that the administration of TRAIL and orlistat is considered a promising strategy for cancer therapy in HRPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 242. doi:1538-7445.AM2012-242

Activity of different anthracycline formulations in hormone‐refractory prostate cancer cell lines: Role of golgi apparatus

The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of doxorubicin (DX), pegylated liposomal DX (PLDX), and non-pegylated liposomal DX (NPLDX) in DU145 and taxane-resistant DU145-R HRPC cell lines. Drug activity and incorporation, apoptosis, and expression of cell death-related markers were evaluated by SRB test, cytofluorimetric assays, and Western blot, respectively. Among the different DX formulations, NPLDX showed the highest cytotoxic activity in both cell lines, with more than 50% of apoptotic cells at only 1/10 of the plasma peak concentration after 72 h exposure. Anthracyclines, in particular NPLDX, were highly concentrated in the Golgi apparatus. Moreover, a significant increase was observed in the expression of CD95 receptor, GD3 ganglioside and, caspase-2 and -8 active forms in both cell lines followed by caspase-3 activation and mitochondrial membrane depolarization. The Golgi apparatus, probably acting as a stress sensor, intensified the conventional apoptotic mechanism induced by anthracyclines. Our data support the hypothesis that organelle-dependent initiation of cell death other than that induced by mitochondria and nucleus is a research area worthy of pursuing and suggest that the Golgi apparatus could be an ideal target for anti-cancer therapy. Of note, the activity of NLPDX in taxane-resistant DU145-R cells warrants further evaluation as second-line treatment of advanced HRPC after taxane failure.

Synthesis and initial tumor affinity testing of iodine-123 labelled EGFR-affine agents as potential imaging probes for hormone-refractory prostate cancer

The epidermal growth factor receptor (EGFR) is over-expressed in a variety of human cancers, including in hormone-refractory prostate carcinomas, in which the EGFR has been associated with advanced disease stage, resistance to standard treatment and poor prognosis. Therefore, the EGFR is considered to be a promising molecular target for molecular imaging and therapy for hormone-refractory prostate cancer. This work describes the synthesis and initial tumor affinity testing of the EGFR antagonist 123I-mAb425 and the EGF receptor tyrosine kinase (EGFR-TK) inhibitor 123I-PD153035 as potential imaging probes for studying EGFR-expressing prostate cancer using single photon emission tomography. Methods 123I-mAb425 and 123I-PD153035 were prepared, starting from the IgG2a antibody and EGFR antagonist mAb425, that binds to the external domain of the EGF receptors, and from the EGFR-TK inhibitor PD153035, targeting the intra-endothelial tyrosine kinase domain of the EGFR, respectively. The potential of 123I-mAb425 and 123I-PD153035 to target EGFR-positive prostate carcinoma was tested on androgen-insensitive PC-3 and DU-145 prostate carcinoma cell lines, and on the androgen-sensitive LNCaP prostate cancer cell line for comparison. In vivo, the capability of 123I-mAb425 and 123I-PD153035 to target hormone-refractory prostate cancer was assessed in RNU rats or nu/nu mice bearing human PC3 prostate cancer xenografts. Results 123I-mAb425 was obtained in >90% radiochemical yield using the IODO-GEN ® method. 123I-PD153035 was synthesized by a non-isotopic [ 123I]iodo-debromination of PD153035 in 50–60% radiochemical yield in a total synthesis time including HPLC separation of 70 min. In vitro 123I-mAb425 and 123I-PD153035 accumulated highly in human PC-3 and DU-145 prostate cancer cells. Radioactivity incorporation into PC-3 and DU-145 tumor cells following 15-min incubation at 37 °C varied from 25% to 48% of the total loaded activity per 10 6 tumor cells (560–1230 cpm/1000 cells). In comparison, the uptake of the EGFR-affine probes into LNCaP prostate carcinoma cells was significantly low (105 ± 25 cpm/1000 cells). Inhibition experiments revealed that 123I-mAb425 is taken up into tumor cells via the same pathway as the naturally occurring epidermal growth factor (EGF), while 123I-PD153035 accumulation in prostate cancer cells occurs presumably via the same pathway as the selective EGFR-Tyrosine kinase antagonist AG1418. In vivo, the human prostate cancer xenografts in mouse war accurately visualized after i.v. administration of 123I-mAb425 by a gamma camera. Conclusion These data suggest that 123I-mAb425 and 123I-PD153035 are promising candidates as imaging probes for EGFR-positive prostate cancer and warrant further in vivo validations to ascertain their potential as imaging agents for clinical used.

Efficacy of combined docetaxel and bevacizumab treatment in hormone-refractory metastatic prostate cancer pretreated with docetaxel: A single institution experience.

e15150 Background: Although taxanes represent the most active agents for the first-line treatment of metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress while receiving taxane-based treatments. No agents are currently approved for second-line therapy in HRPC. Methods: Seven patients with HRPC, pre-treated with docetaxel received combination therapy with bevacizumab (15 mg/kg) and docetaxel (60 mg/m2) every 3 weeks. The inclusion criteria were: age >18 years, World Health Organization performance status 0-1, histologically confirmed adenocarcinoma of prostate, metastatic disease shown by either CT scan or bone scan, previous hormonal therapy with LHRH and anti-androgen combined and progression on chemotherapy with docetaxel as first line treatment. Progression was defined as >50% increase in PSA on two determinations in two weeks apart. The response criteria is defined as with measurement of PSA on two separate occasions with two weeks apart as follows: 1) major PSA response was defined as a reduction from baseline of ≥50%, 2) minor response was defined as a ≥25% to 49%, 3) stable disease defined as to a <25% PSA response, 4) progression defined as more than 25% increase. Results: The study was carried out from July 2006 till Dec 2009. The mean age of our patients was 72.3 years (range 51-82 years). The mean duration of combination treatment was 5.4 months (range 2-9 months). Three patients (43%) had major PSA response; three patients (43%) had minor PSA response while one patient (14%) had disease progression on combination therapy. Two partial responders had thrombocytopenia due to which the treatment was discontinued and two patients experienced grade 1-2 anorexia. No evidence of headaches, proteinuria, hematuria or bleeding was observed. Conclusions: Our results show that the combination of bevacizumab and docetaxel is an active regimen in HRPC after failure on treatment with docetaxel. Platelet counts should be monitored during the therapy. These promising results may provide a basis for further research in a large multicenter trial. No significant financial relationships to disclose.

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA.

Docetaxel–ST1481 sequence exerts a potent cytotoxic activity on hormone‐resistant prostate cancer cells by reducing drug resistance‐related gene expression

The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone-resistant prostate cancer (HRPC) cell lines. The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR. Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes. Our results show that the Doc --> ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second-line treatment of hormone-refractory prostate cancer.

Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer

e16026 Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m2) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (&gt; 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of &gt;10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. No significant financial relationships to disclose.

Lycopene for Advanced Hormone Refractory Prostate Cancer: A Prospective, Open Phase II Pilot Study

We investigated the influence of lycopene on the clinical and laboratory course in men with hormone refractory prostate cancer. To our knowledge this study represents the first time that subjective assessments of the course of therapy have been recorded. We performed a prospective, open phase II pilot study, in which patients with progressive hormone refractory prostate cancer were included. Lycopene supplementation (15 mg) was given daily for 6 months. Followup laboratory tests and clinical examinations were done monthly. Changes to analgesic use and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30) were measured. The study end point was a significant change in serum prostate specific antigen, clinical progression or the end of the 6-month observation period. A total of 18 patients 64 to 85 years old (median age 73) were enrolled in the study during a 20-month period, of whom 17 could be analyzed. Five of the 17 patients (29%) withdrew from the study prematurely, including 4 of 5 because of prostate specific antigen progression and/or tumor associated complications, and 1 due to an allergic reaction to lycopene. Median prostate specific antigen doubled in 6 months from 42.7 ng/ml (range 13.8 to 521.6) in 17 patients to 96.4 ng/ml (range 13.5 to 1,240) in 12. Stable prostate specific antigen was observed in 5 of 17 patients (29%). None of the patients had a greater than 50% decrease in prostate specific antigen. Patients experienced a slight deterioration in mean health status at the end of the study compared to the outset. However, two-thirds of the patients experienced an improved or unchanged situation regardless of the clinical and biochemical course. No clinically relevant benefits were shown for patients with advanced stages of the disease.

7 INVITED Developing combination therapies for hormone-refractory prostate cancer in a pre-clinical mouse model of the disease

7 INVITED Developing combination therapies for hormone-refractory prostate cancer in a pre-clinical mouse model of the disease

Therapeutic Efficacy of Curcumin/TRAIL Combination Regimen for Hormone-Refractory Prostate Cancer

Because of lack of effective treatment options for hormone-refractory prostate cancer at the present time, the need for developing novel therapeutic strategies and targets to treat and prevent the progression of hormone-sensitive prostate cancer to the hormone-refractory stage is paramount. Our previous in vitro studies have shown that curcumin sensitizes both hormone-sensitive and hormone-resistant prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and that combined curcumin/TRAIL treatment induces apoptosis in cancer cells by inhibiting antiapoptotic p-Akt and nuclear factor-kappaB (NF-kappaB). In the present study, we demonstrate that curcumin and TRAIL combination regimen is also the most effective treatment for inhibiting the growth of PC3 xenografts compared to curcumin or TRAIL monotherpy. The inhibition of PC3 tumors by combined treatment correlated with significant reduction in expression of p-Akt and NF-kappaB in tumor tissue. Furthermore, tumor growth inhibition by curcumin/TRAIL combination regimen was associated with significant decrease in cell proliferation and an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the tumors without significant change in microvessel density. Based on the significant efficacy in this preclinical model, combined curcumin/TRAIL regimen may be an effective adjuvant therapy for hormone-refractory prostate cancer.

Biweekly Doxorubicin/Ketoconazole as Second-Line Treatment in Docetaxel-Resistant, Hormone-Refractory Prostate Cancer

Docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. Nevertheless, the prognosis subsequent to progression after first-line therapy is poor and no second-line treatment has been established. A total of 34 patients with androgen-independent prostate cancer received doxorubicin, 30 mg/m(2), every 2 weeks and ketoconazole daily, 400 mg orally every 8 hours. All patients had been treated with docetaxel and had disease progression within 6 months after completion of first-line treatment. Of the 32 evaluable patients, 13 (43.7%, 95% confidence interval [CI] 26.3% to 62.3%) had a prostate-specific antigen (PSA) response, and 4 (28%, 95% CI 8.4% to 58.1%) of 14 patients with measurable disease had a response to therapy. The median time to progression (TTP) was 3.9 months (95% CI 2.0 to 5.9), and the median overall survival (OS) was 13 months (95% CI 8.7 to 17.3). Toxicity was mild, with only 4 cases of nonhematologic grade 3 or 4 toxicity. The most frequent toxicity was nail changes (33 of 34 patients), which was mainly grade 1 (30 cases). The combination of biweekly doxorubicin and ketoconazole is an effective, well-tolerated, second-line therapy for hormone-refractory prostate cancer.

Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study

ObjectiveAlthough the taxanes represent the most active agents for the first-line treatment of metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress while receiving taxane-based treatments. No agents are approved for second-line therapy in HRPC, but common standard practice for the oncologists is to treat patients also after docetaxel failure. MethodsTwenty highly pretreated patients with HRPC received bevacizumab (10mg/kg) and docetaxel (60mg/m2) every 3 wk. All patients had bone metastases and eight had measurable lesions. ResultsEleven patients (55%) had major prostate-specific antigen (PSA) responses, and 3 (37.5%) had objective responses. Seven major PSA responses were recorded in the same patients who had reported a >50% PSA decrease after first-line docetaxel. However, four major PSA responses were observed in patients previously nonresponsive to docetaxel alone. The treatment was well tolerated. ConclusionsOur results show that the combination of bevacizumab and docetaxel is active and well tolerated. Continued investigation of bevacizumab with cytotoxic chemotherapy is warranted in HRPC.

Promising Novel Cytotoxic Agents and Combinations in Metastatic Prostate Cancer

Interest in investigating cytotoxic therapy has increased dramatically since a survival advantage was demonstrated in 2 phase III trials investigating docetaxel-based therapy in hormone-refractory prostate cancer. This result led to an expansion in research in this area with several ongoing trials evaluating docetaxel-based combinations and new cytotoxic agents.

Long-Term Outcome of Phase I/II Clinical Trial of Ad-OC-TK/VAL Gene Therapy for Hormone-Refractory Metastatic Prostate Cancer

We evaluated the long-term safety and efficacy of Ad-OC-TK (recombinant adenoviral vector carrying an osteocalcin promoter-driven herpes simplex virus thymidine kinase gene) plus VAL (valacyclovir) gene therapy for hormone-refractory prostate cancer. Ad-OC-TK/VAL therapy is the first in vivo adenovirus-mediated gene therapy to be used to treat metastatic prostate cancer, including bone metastasis. Six patients were enrolled in this trial, and two doses of Ad-OC-TK (2.5 x 10(9) or 2.5 x 10(10) plaque-forming units) were injected into locally recurrent tumor or bone metastasis on day 1 and day 8. Patients were also given VAL (3 g/day) for 21 days. Safety and efficacy were evaluated for at least 8 months in each patient. All patients tolerated this therapy with no serious adverse events. One prostate-specific antigen (PSA) response (from 318.3 to 4.9 ng/ml) was observed with a time to PSA progression (TTP) of 12 months. Docetaxel (30 mg/m2 per week) and estramustine (560 mg/day) combination chemotherapy (DE) was given to three docetaxel-naive patients on PSA failure after gene therapy. All three patients had a PSA response to DE therapy with 21, 7, and 4 months of TTP. These results suggest that additional trials are warranted.

Management of hormone refractory prostate cancer

This review highlights the most interesting developments and outstanding issues surrounding the management of hormone-refractory prostate cancer published in the medical literature during the past year. Recent research has reported poor health-related quality-of-life outcomes for patient with hormone-refractory prostate cancer treated in standard clinical practices. In addition, age-related differences in survival appear to exist for patients with hormone-refractory prostate cancer. Two potential future therapies for hormone-refractory prostate cancer, sipuleucel-T and the combination regimen of docetaxel and DN-101, demonstrate promising preliminary clinical data in terms of improving survival while minimizing toxicity. A variety of novel agents has been tested for hormone-refractory prostate cancer, including pertuzumab and BMS-275291, which may stabilize disease with minimal toxicity. In terms of bone-related health, skeletal-related events have been found to be associated with worse survival and health-related quality of life outcomes. Data reported during the past year have implications for future research directions. This direction includes the need for continued exploration of health-related quality of life and age-related outcomes, further study of the disease-stabilizing effects of novel therapies and their translation into improved survival, as well as directed efforts to continue preventing skeletal-related events, which may impact survival and health-related quality of life.

Androgen Receptor– and E2F-1–Targeted Thymoquinone Therapy for Hormone-Refractory Prostate Cancer

Relapse of prostate cancer after androgen ablation therapy is hormone-refractory, with continued tumor growth being dependent on the androgen receptor (AR). E2F-1, a regulator of cell proliferation and viability, reportedly plays a role in the development of hormone-refractory prostate cancer. Thymoquinone is a component of Nigella sativa, an herb used for thousands of years for culinary and medicinal purposes in Asian and Middle Eastern countries and has been reported to have an antineoplastic effect both in vitro and in vivo. We observed that thymoquinone inhibited DNA synthesis, proliferation, and viability of cancerous (LNCaP, C4-B, DU145, and PC-3) but not noncancerous (BPH-1) prostate epithelial cells by down-regulating AR and E2F-1. In LNCaP cells, this was associated with a dramatic increase in p21(Cip1), p27(Kip1), and Bax. Thymoquinone blunted progression of synchronized LNCaP cells from G1 to S phase, with a concomitant decrease in AR and E2F-1 as well as the E2F-1-regulated proteins necessary for cell cycle progression. In a xenograft prostate tumor model, thymoquinone inhibited growth of C4-2B-derived tumors in nude mice. This in vivo suppression of tumor growth, as with C4-2B cell growth in culture, was associated with a dramatic decrease in AR, E2F-1, and cyclin A as determined by Western blot of tissue extracts. Tissue immunohistochemical staining confirmed a marked reduction in E2F-1 and showed induction of apoptosis on terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. These findings show that thymoquinone suppresses the expression of AR and E2F-1 necessary for proliferation and viability of androgen-sensitive as well as androgen-independent prostate cancer cells both in vitro and in vivo and, moreover, produced no noticeable side effects in mice. We conclude that thymoquinone, a naturally occurring herbal product, may prove to be effective in treating hormone-sensitive as well as hormone-refractory prostate cancer. Furthermore, because of its selective effect on cancer cells, we believe that thymoquinone can also be used safely to help prevent the development of prostate cancer.

Molekulare Grundlagen alternativer Therapieansätze für das hormonrefraktäre Prostatakarzinom

Prostate cancer is more frequently diagnosed in men from Western countries than from Asian societies. Therefore, nutritional factors such as phyto-oestrogens from soya are considered to cause this prostate cancer prevention effect. As there is no curative therapy for hormone-refractory prostate cancer, new strategies are in demand which might include phyto-oestrogens or inhibitors of histone deacetylases. Both approaches have in common the potential to reduce the aberrant androgen receptor and IGF receptor signalling. Furthermore, invasiveness and acquired survival strategies of tumours can be diminished. Reduced tumour cell proliferation and PSA secretion coincide with altered gene expression in the aforementioned processes. In addition, selective knock-down of genes by RNA interference afforded functional analyses regarding impact and succession of expression events involved in the beneficial effects caused by phyto-oestrogens and histone deacetylase inhibitors.