minocycline and Ovarian-Neoplasms

Interleukin (IL)-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK)1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2)-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130) and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h) of minocycline (30 mg/kg) led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP)-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer.

Topics: Active Transport, Cell Nucleus; Animals; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Nucleus; Estrogens, Catechol; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-1beta; Interleukin-6; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Minocycline; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Invasiveness; Ovarian Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Receptors, Interleukin-6; Signal Transduction; STAT3 Transcription Factor

Substantial evidence supports the critical role of NF-κB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-κB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-κB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-κB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IκBα kinase (IKK) activation, IκBα phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-β-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-β and TAK1. Further studies demonstrated that minocycline downregulated TGF-β1 expression. Enforced TGF-β1 expression induced NF-κB activity, and minocycline rescued this effect. Consistent with this finding, TGF-β1 knockdown suppressed NF-κB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-κB activity is mediated, in part, through inhibition of TGF-β1. Furthermore, the influence of minocycline on NF-κB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-κB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-β-NF-κB axis in ovarian cancer.. This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline.

Topics: Animals; Cell Line, Tumor; Female; Humans; I-kappa B Proteins; MAP Kinase Kinase Kinases; Mice; Mice, Inbred BALB C; Mice, Nude; Minocycline; Molecular Targeted Therapy; NF-kappa B; Ovarian Neoplasms; Signal Transduction; Transforming Growth Factor beta1; Xenograft Model Antitumor Assays

To evaluate the effect of minocycline on the expression of cytokines and growth factors responsible for malignant ascite formation.. In vitro, cells obtained from malignant ascites were pre-treated with minocycline (0-100 μmol/L) and exposed briefly to hypoxia. In vivo, female nude mice bearing OVCAR-3 tumors were treated orally in drinking water with minocycline for 4 weeks. Plasma, ascites, and tumors were analyzed.. Minocycline blocked hypoxia-induced surge in interleukin-6 (IL-6), its soluble receptor (sIL-6R) and vascular endothelial growth factor (VEGF) levels in concentration-dependent manner. In mice, orally administered minocycline led to dramatic reduction in tumor weight and malignant ascite volume. IL-6, sIL6R and in particular VEGF levels were highly suppressed in plasma, ascite fluid and tumor tissue by minocycline. In addition, tumors from minocycline treated mice expressed profoundly lower levels of phosphorylated extracellular regulated kinases (p-Erk1/2) and p-Akt. Minocycline was also effective at suppressing transforming growth factor beta (TGF-β1) and increasing vascular endothelial cadherin (VE-cadherin) expression thereby providing molecular confirmation for its effects on malignant ascite formation.. Orally administered minocycline is highly effective in suppressing ovarian cancer-induced malignant ascites by targeting cytokines and growth factors essential for tumor growth and malignant ascite formation.

Topics: Animals; Ascites; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Interleukin-6; Mice; Minocycline; Ovarian Neoplasms; Proto-Oncogene Proteins c-akt; Receptors, Interleukin-6; Signal Transduction; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

These studies were designed to determine whether minocycline inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved.. The effect of minocycline on ovarian cancer cell proliferation, cell cycle progression and apoptosis was assessed using human ovarian cancer cell lines OVCAR-3, SKOV-3 and A2780. Then, the capacity of minocycline to inhibit growth of OVCAR-3 xenografts in female nude mice was examined.. Minocycline inhibited cell proliferation and colony formation, down-regulated cyclins A, B and E leading to arrest of cells in the G(0) phase of the cycle and suppression of DNA synthesis. Furthermore, exposure of these cells to minocycline led to DNA laddering, activation of caspase-3 and cleavage of PARP-1. In nude mice bearing sub-cutaneous tumors, minocycline suppressed tumor proliferation index, angiogenesis and tumor growth.. These findings provide the initial basis for further evaluation of minocycline in the treatment of ovarian cancer.

Topics: Animals; Apoptosis; Carcinoma, Ovarian Epithelial; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cyclins; DNA, Neoplasm; Female; Humans; Mice; Mice, Nude; Minocycline; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Survival Rate; Xenograft Model Antitumor Assays

The purpose of this study was to describe our experience with ultrasound-guided aspiration of postoperative pelvic lymphocysts followed by intracavitary minocycline injection as sclerotherapy.. From 1997 to 2003, patients who developed either symptomatic or persistent lymphocyst after pelvic lymphadenectomy for gynecological malignancy were recruited in this study. All of the lymphocysts were palpable and were further examined by ultrasonography. Percutaneous ultrasound-guided needle aspiration of the lymphocyst was performed and then immediately followed by a single-dose injection of minocycline into the collapsed cavity. Follow-up was conducted every 4 weeks with pelvic examination and ultrasonography.. Nineteen patients with a total of 21 pelvic lymphocysts underwent this procedure. The median size of the lymphocysts was 6 cm in diameter (range, 4-9 cm). Fifteen patients received 1 treatment, 3 received 2, and 1 patient with bilateral lymphocysts received 3 treatments. Complete resolution occurred in 14 patients (74%), and the other 5 patients (26%) had partial resolution with the volume of the lymphocyst decreasing at least 50%. For the 14 patients with complete resolution, the median time from treatment to disappearance of the lymphocyst was 3 months (range, 1-10 months), and none of them developed recurrence during the average follow-up period of 40 months (range, 2-62 months). No significant complication occurred with this procedure except for transient mild to moderate pelvic pain.. Minocycline sclerotherapy seems to be a simple and safe method with a satisfactory success rate in treating lymphocysts which develop after pelvic lymphadenectomy. It can be performed in an outpatient setting and can be repeated if necessary. This procedure may be considered as the initial treatment modality for patients suffering from symptomatic or persistent lymphocysts after radical gynecological surgery.

Topics: Adult; Aged; Cysts; Endometrial Neoplasms; Female; Humans; Lymph Node Excision; Lymphatic Diseases; Middle Aged; Minocycline; Ovarian Neoplasms; Pelvic Pain; Pelvis; Sclerotherapy; Suction; Ultrasonography; Uterine Cervical Neoplasms