Docetaxel Chemotherapy In Prostate Cancer Research Articles

Ferroptosis Induction Improves the Sensitivity of Docetaxel in Prostate Cancer.

Docetaxel resistance seriously affects its clinical application in prostate cancer (PCa). Ferroptosis is a type of iron-dependent cell death driven by lipid peroxidation. It has been recently found that ferroptosis influences various biological processes. However, the potential role of ferroptosis in docetaxel chemotherapy for PCa is still elusive. In this study, we aimed to explore whether altering the level of ferroptosis can affect docetaxel sensitivity in PCa. The results indicated that docetaxel promoted ferroptotic cell death in several PCa cells, and ferroptosis inducers, erastin, and RSL3 markedly increased the cytotoxic effect of docetaxel. Furthermore, our results showed that ferroptosis resistance was closely associated with docetaxel insensitivity in PCa-resistant cells. Erastin or RSL3 rendered resistant PCa cells susceptible to docetaxel, with elevated levels of lipid ROS and decreased protein expression of GPX4 and SLC7A11. Moreover, treatment with erastin and RSL3 led to significant suppression of resistant tumors, and the combination of RSL3 with docetaxel significantly halted tumor growth in vivo when compared with either drug. Taken together, our findings indicate that ferroptosis is involved in docetaxel resistance, and its inducers are promising therapeutic strategies for advanced PCa.

Hypersensitivity Reactions in Men with Prostate Cancer Undergoing Docetaxel Chemotherapy

Purpose: To review hypersensitivity reactions in men receiving docetaxel chemotherapy for prostate cancer using a conservative steroid schedule.

ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer

BackgroundThe efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate...

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

Introduction: High baseline YKL-40 serum levels are associated with drug resistance in several solid tumours. However, their role in predicting docetaxel (DOC) resistance in prostate cancer (PCa) is unknown. Methods: Pre-treatment serum levels of YKL-40 and prostate-specific antigen (PSA) were analyzed in 109 castration-resistant prostate cancer patients who underwent DOC-therapy. Responsive patients were retreated by repeated series of DOC. Results were compared with the clinical parameters as well as overall (OS) and disease-specific survival (DSS). Results: YKL-40 but not PSA serum levels were significantly higher in patients with baseline resistance to DOC (p = 0.035). Higher YKL-40 and PSA levels were detected in patients with bone metastasis (p = 0.032; p = 0.010) and in those who were not pre-treated with radical prostatectomy (p = 0.011, p = 0.008). High YKL-40 levels were associated with shorter OS (p = 0.037) and DSS (p = 0.017) in patients who received DOC in the first-line setting. In multivariable analysis, ECOG performance status (p = 0.009), presence of any metastases (p = 0.016) and high PSA levels (p = 0.005) remained independent predictors for DSS. Conclusions: YKL-40 may help to identify patients with baseline resistance to DOC and therefore may help to optimize treatment decisions. In accordance, high pre-treatment YKL-40 serum levels were associated with shorter OS and DSS in patients who received DOC as first-line therapy.

Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer

Background:Docetaxel is the only FDA-approved first-line treatment for castration-resistant prostate cancer (CRPC) patients. Docetaxel treatment inevitably leads to tumour recurrence after an initial therapeutic response with generation of multinucleated polyploid (MP) cells. Here we investigated role of MP cells in clinical relapse of CRPC.Methods:Prostate cancer (PC-3) cells were treated with docetaxel (5 nM) for 3 days followed by a washout and samples were collected at close intervals over 35 days post drug washout. The tumorigenic potential of the giant MP cells was studied by implanting MP cells subcutaneously as tumour xenografts in nude mice.Results:Docetaxel-induced polyploid cells undergo mitotic slippage and eventually spawn mononucleated cells via asymmetric cell division or neosis. Both MP and cells derived from polyploid cells had increased survival signals, were positive for CD44 and were resistant to docetaxel chemotherapy. Although MP cells were tumorigenic in nude mice, these cells took a significantly longer time to form tumours compared with parent PC-3 cells.Conclusions:Generation of MP cells upon docetaxel therapy is an adaptive response of apoptosis-reluctant cells. These giant cells ultimately contribute to the generation of mononucleated aneuploid cells via neosis and may have a fundamental role precipitating clinical relapse and chemoresistance in CRPC.

Abstract B19: Vascular normalization suppresses tumor progression and potentiates docetaxel chemotherapy in prostate cancer

Abstract Background: Tumor requires excessive oxygen and nutrients due to their rapid growth. Tumor is generally vascular but the vasculature is not physiologic but leaky, dilated, and tortuous. The inefficiency of tumor vessels induces hypoxic stress that makes the tumor more aggressive. Here, we investigated the role of normalizing tumor vasculature on tumor progression and treatment efficacy of conventional chemotherapy in prostate cancer. Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of SAC-1004 on endothelial cells. Immunofluorescent confocal imaging with immunocytochemistry was performed for E-cadherin expression in HUVECs. MTS assay was performed to assess cell proliferation of HUVECs and PC-3 cells after SAC-1004 treatment. Immunohistochemical staining with anti-CD31 and anti-SMA antibodies was performed to assess vasculature in vivo. PC-3 subcutaneous xenografts were developed to evaluate the effects of SAC-1004 on tumor vasculature and tumor growth in prostate cancer. Magnetic resonance images were taken to assess vascular perfusion in xenografts. SAC-1004 was administrated via tail vein once a day for 7 days. Docetaxel was administrated intravenously once a week. Results: SAC-1004 restored junction protein E-cadherin in vitro in endothelial cells and significantly reduced VEGF-induced retinal vascular leakage. SAC-1004 promoted proliferation of HUVECs in vitro in a dose-dependent manner. However, proliferation of cancer cells was not significantly affected by SAC-1004 treatment. Reduced vascular leakiness and improved hypoxia were found in PC-3 xenografts treated with SAC-1004 treatment and magnetic resonance imaging after SAC-1004 treatment for 7 days confirmed improved perfusion in the PC-3 xenografts treated with SAC-1004 compared with control. Interestingly, SAC-1004 treatment suppressed tumor growth in PC-3 xenografts but SAC-1004 followed by intravenous docetaxel treatment showed the most potent tumor suppression compared with control in PC-3 xenografts. Conclusions: SAC-1004 improves hypoxic tumor microenvironment and restores abnormal leak vasculature of tumor by restoring endothelial cell junction in prostate cancer. Vascular normalization induced tumor regression and docetaxel combination following vascular normalization sensitized prostate cancer to docetaxel treatment. Citation Format: You Hyun Kang, Hyun A Jin, Jun Hyeok Heo, Ki Hong Kim, Kyung Seok Han, Sung Joon Hong. Vascular normalization suppresses tumor progression and potentiates docetaxel chemotherapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B19.

Abstract B12: Endothelial stabilizer SAC-1004 normalizes tumor vasculature and potentiates docetaxel chemotherapy in prostate cancer

Abstract Background: Since tumor requires excessive oxygen and nutrients due to their rapid growth, tumor is generally vascular. However, tumor vasculature is not physiologic but leaky, dilated, and tortuous. The inefficiency of tumor vessels in terms of perfusion induces hypoxic stress that makes the tumor more aggressive. Here, we investigated the role of a novel endothelial stabilizer SAC-1004 on tumor vascular normalization and its effects on tumor growth in prostate cancer. Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of SAC-1004 on endothelial cells. Immunocytochemical staining and immunofluorescent confocal imaging was performed for E-cadherin expression in HUVECs. MTS assay was performed to assess cell proliferation of HUVECs and PC-3 cells after SAC-1004 treatment. Immunohistochemical staining with anti-CD31 and anti-SMA antibodies was performed to assess vasculature in vivo. PC-3 subcutaneous xenografts were developed to evaluate the effects of SAC-1004 on tumor vasculature and tumor growth in prostate cancer. Magnetic resonance images were taken to assess vascular perfusion in xenografts. SAC-1004 was administrated via tail vein once a day for 7 days. Docetaxel was administrated intravenously once a week. Results: SAC-1004 restored junction protein E-cadherin in vitro in endothelial cells and significantly reduced VEGF-induced retinal vascular leakage. SAC-1004 promoted proliferation of HUVECs in vitro in a dose-dependent manner. However, proliferation of cancer cells was not significantly affected by SAC-1004 treatment. Reduced vascular leakiness was found in PC-3 xenografts treated with SAC-1004 treatment and magnetic resonance imaging after SAC-1004 treatment for 7 days confirmed improved perfusion in the PC-3 xenografts treated with SAC-1004 compared with control. Interestingly, SAC-1004 treatment suppressed tumor growth in PC-3 xenografts but SAC-1004 followed by intravenous docetaxel treatment showed the most potent tumor suppression compared with control in PC-3 xenografts. Conclusions: SAC-1004 restored abnormal leak vasculature of tumor by restoring endothelial cell junction in prostate cancer. Vascular normalization by SAC-1004 induced tumor regression and combination with docetaxel following vascular normalization potentiated anti-tumor effects of docetaxel in prostate cancer. Citation Format: Yoo Hyun Kang, Jun Hyeok Heo, Hyun A Jin, Ki Chung Park, Sung Joon Hong, Kyung Seok Han. Endothelial stabilizer SAC-1004 normalizes tumor vasculature and potentiates docetaxel chemotherapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B12.

Abstract 982: Malate dehydrogenase 2 confers resistance to docetaxel chemotherapy in prostate cancer through JNK pathway

Abstract Resistance to chemotherapy represents a significant obstacle in cancer therapeutics. Novel mechanistic understandings in cancer cell chemotherapeutic sensitivity and resistance can optimize treatment and improve patient outcome. Molecular alterations in the metabolic pathways are associated with cancer development; however, the role of these alterations in chemotherapy efficacy is largely unknown. In this study, we identified a novel role for mitochondrial malate dehydrogenase 2 (MDH2) in mediating prostate cancer resistance to docetaxel-chemotherapy. We performed gene expression microarray analyses on frozen needle biopsies from prostate cancer patients before they underwent neoadjuvant chemotherapy. We observed that genes in the metabolic pathways are significantly altered in the cancer epithelium versus the matched- tumor adjacent benign epithelium. In addition, some of the metabolic gene expression alterations are associated with the long-term treatment outcome. Patients with MDH2 overexpression in cancer cells had a significantly lower relapse-free survival (RFS) based on the Kaplan-Meier analysis. To investigate the underlying mechanism responsible for this clinical observation, we found that MDH2 expression was elevated in prostate cancer cell lines compared to benign prostate epithelial cells. Then we established stable MDH2 knock-down prostate cancer lines and evaluated cell proliferation and cell viability within the context of chemotherapy. We found that MDH2 knockdown significantly enhanced the docetaxel sensitivity in prostate cancer cell lines LNCaP, C42B and PC3. Metabolic and redox measurement showed that MDH2 knockdown significantly reduced cellular ATP levels and increased the ADP/ATP and NAD+/NADH level. In addition, MDH2 knockdown significantly increased reactive oxygen specifies (ROS) while maintaining the oxygen consumption rate. These metabolic alterations were associated with the sustained activation of JNK signaling cascade after docetaxel treatment and the inactivation of apoptosis inhibitor BCL2. Taken together, these data suggest a novel function for MDH2 in prostate cancer development and chemotherapy, in which the cancer associated metabolic and redox alteration confers resistance to chemotherapy by regulating pathways of signal transduction and cell death. 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 982. doi:1538-7445.AM2012-982

Resolution of Thrombocytopenia Secondary to Disseminated Intravascular Coagulation With Docetaxel Chemotherapy in Prostate Cancer

Patients with metastatic hormone-refractory prostate carcinoma may have dramatic and life-threatening coagulation complications from their disease. They are at risk for either clotting or bleeding events. We report the case of a man with metastatic castration-resistant prostate cancer with disseminated intravascular coagulation who had both clotting and bleeding in addition to thrombocytopenia. The patient did not respond to supportive therapy and was treated with docetaxel despite a platelet count of 46/mm³. The treatment resulted in resolution of disseminated intravascular coagulation, normalization of the platelet count, and resolution of hematuria. We review disseminated intravascular coagulation in prostate cancer and different possible treatments.

Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

BackgroundReovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication.MethodsThe effects of reovirus and chemotherapy on in vitro cytotoxicity were investigated in PC3 and Du 145 cells and the interactions between agents were assessed by combination index analysis. An Annexin V/propidium iodide fluorescence-activated cell sorting-based assay was used to determine mode of cell death. The effects of reovirus and docetaxel administered as single agent or combination therapy were tested in vivo in a murine model. The effects of docetaxel and reovirus, alone and together, on microtubule stabilisation were investigated by Western blot analysis.ResultsVariable degrees of synergistic cytotoxicity were observed in PC3 and Du 145 cells exposed to live reovirus and several chemotherapy agents. Combination of reovirus infection with docetaxel exposure led to increased late apoptotic/necrotic cell populations. Reovirus/docetaxel combined therapy led to reduced tumour growth and increased survival in a PC3 tumour bearing mouse model. Microtubule stabilization was enhanced in PC3 cells treated with reovirus/docetaxel combined therapy compared to other reovirus/chemotherapy combinations.ConclusionsThe co-administration of a variety of chemotherapeutic agents with live reovirus was able to enhance cytotoxicity synergistically in vitro. The combination of docetaxel with reovirus also delayed tumour growth and improved survival in vivo. Enhanced microtubule stabilisation following this combination treatment may, in part, explain the mechanism of synergy. These results provide evidence to support the ongoing clinical trials using these agents.

Efficacy of abiraterone acetate in post-docetaxel castration-resistant prostate cancer

Evaluation of: Reid AH, Attard G, Danila DC et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J. Clin. Oncol. 28(9), 1489–1495 (2010).Inhibition of cytochrome P17 (CYP17), which is involved in androgen synthesis, is a promising therapeutic strategy for castration-resistant prostate cancer (CRPC). The first multicenter, Phase II study of a CYP17 inhibitor, the small molecule abiraterone acetate, has been conducted on 47 patients that received prior docetaxel chemotherapy for prostate cancer. With 1000 mg once daily, declines of more than 50% in prostate-specific antigen and circulating tumor cell counts were seen in 51 and 63% of patients, respectively. Overall, the drug was well tolerated and had a significant antitumor activity with symptomatic improvements. Reid and colleagues’ study highlights abiraterone as a key molecule in CRPC treatment and gives further evidence of the involvement of the androgen receptor signaling axis in the disease. A randomized Phase III trial is ongoing to define the prognostic impact of this drug among the very limited arsenal of drugs currently available for CRPC. In the meantime, other CYP17 inhibitors are expected to show a favorable safety and efficacy profile, as are other novel powerful agents and combinatorial therapeutic strategies.

ドセタキセル療法により強皮症様皮膚硬化を呈したホルモン不応性前立腺癌の１例

We report the first case of scleroderma-like skin sclerosis induced by docetaxel chemotherapy for prostate cancer in Japan. A 67-year-old man underwent radical prostatectomy for cT3aN0M0 prostate cancer in 2003. Thereafter PSA recurrence developed and antiandrogen deprivation therapy was used. However, we diagnosed this case as hormone refractory prostate cancer and began docetaxel chemotherapy in October 2008. There were no nonhematological adverse events through two courses of treatment. He presented to dermatology due to pain and swelling of both upper arms on the second day of the third course. However, when treated with a cooling method, swelling of the upper arms became worse and CPK rose to 1,921 IU/I on the eighth day. We administered a steroid ointment and an antibiotic due to suspicion of thrombophlebitis. Nevertheless, CPK rose to 2,791 IU/I and a skin biopsy was done. In consequence, scleroderma-like skin sclerosis induced by docetaxel chemotherapy was diagnosed. Swelling appeared in both lower limbs and the pain got worse on the 17th day. Therefore docetaxel chemotherapy was discontinued and prednisolone was increased to 30 mg/day, in addition to beginning codeine use for the pain. Thereafter, the painful sclerosis was ameliorated.