Minocycline inhibits malignant ascites of ovarian cancer through targeting multiple signaling pathways

Abstract

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Objectives

To evaluate the effect of minocycline on the expression of cytokines and growth factors responsible for malignant ascite formation.

Methods

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.

Results

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.

Conclusion

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.