Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

SIMPLE SUMMARY: Meningioma is the most common intracranial neoplasm derived from the arachnoid cap cells of the leptomeninges. Malignant meningioma is generally more aggressive than other meningioma and frequently recurs even after surgery and radiation therapy. Clinical trials have been performed on candidate drugs, including everolimus, an inhibitor of mammalian target of rapamycin. However, an effective standard systemic therapy has not yet been established and the prognosis of patients with malignant meningioma is still poor. We recently reported the radiosensitization effects of gemcitabine in malignant meningioma cells, which suggests its potential to enhance the efficacy of candidate drugs for meningioma. In the present study, we demonstrated that gemcitabine enhanced the therapeutic effects of everolimus in malignant meningioma cells, and these effects were further augmented by navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins, both in vitro and in vivo. The present results provide support for the clinical application of gemcitabine and navitoclax in combination with everolimus to the treatment of patients with malignant meningioma. ABSTRACT: Despite several clinical trials with encouraging findings, effective standard systemic therapies have yet to be established for malignant meningioma and the prognosis of these patients remains poor. Accumulating preclinical and clinical evidence suggests that gemcitabine is effective against malignant meningioma. To identify drugs with therapeutic effects that may be enhanced in combination with gemcitabine, we screened drugs that have been tested in preclinical and clinical trials for meningioma. In IOMM-Lee and HKBMM malignant meningioma cells, gemcitabine enhanced the growth inhibitory effects of the mTOR inhibitor everolimus, the clinical benefits of which have been demonstrated in patients with meningioma. The synergistic growth inhibitory effects of this combination were accompanied by cellular senescence characterized by an increase in senescence-associated β-galactosidase activity. To enhance the effects of this combination, we screened senolytic drugs that selectively kill senescent cells, and found that navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins, effectively reduced the number of viable malignant meningioma cells in combination with everolimus and gemcitabine by inducing apoptotic cell death. The suppression of tumor growth in vivo by the combination of everolimus with gemcitabine was significantly stronger than that by either treatment alone. Moreover, navitoclax, in combination with everolimus and gemcitabine, significantly reduced tumor sizes with an increase in the number of cleaved caspase-3-positive apoptotic cells. The present results suggest that the addition of gemcitabine with or without navitoclax to everolimus is a promising strategy that warrants further evaluation in future clinical trials for malignant meningioma.