dehydroxymethylepoxyquinomicin and Prostatic-Neoplasms

Topics: Antineoplastic Agents; Benzamides; Cyclohexanones; Glucocorticoids; Humans; Male; NF-kappa B; Prostatic Neoplasms; Proteasome Inhibitors; Pyrrolidines; Thiocarbamates

Inducible activation of nuclear factor (NF)-κB is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-κB with a novel NF-κB inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy.. PC-3 and LNCaP cells were exposed to irradiation and/or DHMEQ. Cell viability, cell cycle analysis, western blotting assay, and NF-κB activity were measured. The antitumour effect of irradiation combined with DHMEQ in vivo was also assessed.. The combination of DHMEQ with irradiation resulted in cell growth inhibition and G2/M arrest relative to treatment with irradiation alone. Inducible NF-κB activity by irradiation was inhibited by DHMEQ treatment. The expression of p53 and p21 in LNCaP, and of 14-3-3σ in PC-3 cells, was increased in the combination treatment. In the in vivo study, 64 days after the start of treatment, tumour size was 85.1%, 77.1%, and 64.7% smaller in the combination treatment group than that of the untreated control, DHMEQ-treated alone, and irradiation alone groups, respectively.. Blockade of NF-κB activity induced by radiation with DHMEQ could overcome radio-resistant responses and may become a new therapeutic modality for treating prostate cancer.

Topics: Animals; Antineoplastic Agents; Benzamides; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Survival; Cyclohexanones; Humans; Male; Mice; Mice, Nude; NF-kappa B; Prostatic Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays

To investigate the association between serum interleukin-6 (IL-6) and cachexia in patients with prostate cancer and the inhibitory effect of a new nuclear factor kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on IL-6 production and cachexia in an animal model of hormone-refractory prostate cancer.. The association between serum IL-6 levels and variables of cachexia was evaluated in 98 patients with prostate cancer. The inhibitory effects of DHMEQ on IL-6 secretion and cachexia were investigated in in vitro and in vivo studies using JCA-1 cells derived from human prostate cancer.. Serum IL-6 levels were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. IL-6 secretion was significantly inhibited in JCA-1 cells exposed to DHMEQ. Intraperitoneal administration of DHMEQ (8 mg/kg) to tumor-bearing mice produced a significant amelioration of the reduction in body weight, epididymal fat weight, gastrocnemius muscle weight, hematocrit, and serum levels of triglyceride and albumin when compared with administration of DMSO or no treatment. DHMEQ caused a significant decrease of serum IL-6 level in JCA-1 tumor-bearing mice (all P < 0.05).. These results suggested an association between serum IL-6 and cachexia in patients with prostate cancer and in JCA-1 tumor-bearing mice and that a new NF-kappaB inhibitor, DHMEQ, could prevent the development of cachexia in JCA-1 tumor-bearing mice presumably through the inhibition of IL-6 secretion. DHMEQ seems to show promise as a novel and unique anticachectic agent in hormone-refractory prostate cancer.

Topics: Albumins; Animals; Antineoplastic Agents; Benzamides; Body Mass Index; Body Weight; Cachexia; Cell Line, Tumor; Cyclohexanones; Disease Models, Animal; Dose-Response Relationship, Drug; Hematocrit; Humans; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Neoplasm Transplantation; NF-kappa B; Prostatic Neoplasms; Time Factors; Triglycerides; Weight Loss

We have synthesized and explored the feasibility of using a novel nuclear factor (NF) kappaB inhibitor, a dehydroxymethylepoxyquinomicin designated as DHMEQ, against prostate cancer. The activity of NFkappaB, evaluated by transient transfection of a luciferase reporter DNA containing a specific binding sequence for NFkappaB, was inhibited by DHMEQ in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3. Statistically significant growth inhibition was achieved by 20 micro g/ml of DHMEQ, and marked levels of apoptosis were induced 48 h after DHMEQ administration in vitro. Electrophoretic mobility shift assay showed that DHMEQ completely inhibited NFkappaB DNA binding activity in JCA-1 cells. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude mice without any side effects. Our result indicates the possibility of using a novel NFkappaB activation inhibitor, DHMEQ, as a new treatment strategy against hormone-refractory prostate cancer.

Topics: Animals; Apoptosis; Benzamides; Cell Division; Cyclohexanones; Dose-Response Relationship, Drug; Drug Resistance; Humans; Kinetics; Male; Mice; Mice, Nude; NF-kappa B; Prostatic Neoplasms; Tumor Cells, Cultured