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.