ABSTRACT
We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kappaB (NF-kappaB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kappaB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (P<0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (P<0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Dexamethasone/pharmacology , Orchiectomy , Prostatic Neoplasms/blood supply , Taxoids/pharmacology , Animals , Cell Line, Tumor , Docetaxel , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Interleukin-8/biosynthesis , Interleukin-8/metabolism , Male , Mice , NF-kappa B/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Taxoids/therapeutic use , Transcription Factor AP-1/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Hypoxic cancer cells are resistant to treatment, leading to the selection of cells with a more malignant phenotype. The expression of interleukin-8 (IL-8) plays an important role in the tumorigenesis and metastasis of solid tumors including prostate cancer. Recently, we detected elevated expression of IL-8 and IL-8 receptors in human prostate cancer tissue. The objective of the current study was to determine whether hypoxia increases IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. IL-8, CXCR1 and CXCR2 messenger RNA (mRNA) expression in PC3 cells was upregulated in response to hypoxia in a time-dependent manner. Elevated IL-8 secretion following hypoxia was detected by enzyme-linked immunosorbent assay, while immunoblotting confirmed elevated receptor expression. Attenuation of hypoxia-inducible factor (HIF-1) and nuclear factor-kappaB (NF-kappaB) transcriptional activity using small interfering RNA (siRNA), a HIF-1 dominant-negative and pharmacological inhibitors, abrogated hypoxia-induced transcription of CXCR1 and CXCR2 in PC3 cells. Furthermore, chromatin-IP analysis demonstrated binding of HIF-1 and NF-kappaB to CXCR1. Finally, inhibition of IL-8 signaling potentiated etoposide-induced cell death in hypoxic PC3 cells. These results suggest that IL-8 signaling confers a survival advantage to hypoxic prostate cancer cells, and therefore, strategies to inhibit IL-8 signaling may sensitize hypoxic tumor cells to conventional treatments.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia , NF-kappa B/metabolism , Prostatic Neoplasms/metabolism , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8B/genetics , Cell Survival , Chromatin Immunoprecipitation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Immunoblotting , Immunoprecipitation , Interleukin-8/metabolism , Male , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , Prostatic Neoplasms/pathology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/antagonists & inhibitors , Receptors, Interleukin-8B/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Transcription, Genetic , Up-RegulationABSTRACT
Palliative chemotherapy for inoperable/metastatic oesophageal cancer has limited activity. This study assesses the feasibility and activity of gemcitabine and cisplatin in this group of patients. In total, 42 patients with locally advanced/metastatic squamous or adenocarcinoma of the oesophagus were treated with gemcitabine 1250 mg m(-2) days 1 and 8 and cisplatin 75 mg m(-2) day 1 in a 21-day cycle. Interim safety analysis was carried out after the first 19 patients suggested significant toxicity. The dose of gemcitabine was subsequently reduced to 1000 mg m(-2). Patients were assessed for toxicity and response. The median number of treatment cycles per patient was 4 (range 1-6). Grade 3-4 neutropenia occurred in 37% of cycles; however, there was only one episode of neutropenic fever. Nonhaematological toxicities included fatigue, nausea and vomiting. Among 32 patients eligible for response, there were three complete responses and 16 partial responses (overall response rate of 45%); nine patients had stable disease. Median survival was 11 months. The response rate appears to be greatest in those with squamous carcinoma compared to adenocarcinoma (71 vs 33%, P=0.036). The combination of gemcitabine and cisplatin in this schedule has manageable toxicity and significant activity in patients with locally advanced/metastatic oesophageal cancer and is worthy of further study.
