Combination of minocycline with STAT3 inhibitor suppresses glioma cell-derived tumorigenicity

Abstract

Glioblastoma Multiforme (GBM) is the most common incurable primary brain tumor of the central nervous system Glioma stem cells (GSCs) are thought to contribute to recurrence and drug resistance in GBM Minocycline (Mino) is a semisynthetic tetracycline derivative with bacteriostatic activity Our laboratory has reported that Mino induces glioma cells endoplasmic reticulum stress resulting in autophagic cell death However GSCs exhibited higher drug resistance to Mino than Non-GSCs did Signal transducer and activator of transcription 3 (STAT3) affect neurosphere formation and cell viability in GSCs In this study I hypothesized that combination of Mino with STAT3 inhibition exhibited more effective in the treatment of GBM I isolated GSCs from human primary glioblastoma cell line U87 using CD133 as a cancer stem cell marker These CD133+ glioma cells exhibited self-renew property and expressed stem cell markers in vitro promoted tumor formation in vivo Mino reduced the survival rate more in CD133- than in CD133+ cells In contrast STAT3 inhibitor was more effective in reducing the survival rate of CD133+ Combined treatment with Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells Transduced glioma cells were injected intracranially into athymic mice and tumor growth was monitored using the IVIS-200 imaging system Combination therapy of Mino plus STAT3 inhibitor synergistically inhibited tumor growth in nude mice Furthermore I found that combined treatment-induced cell death involved caspase-dependent apoptosis at 48 hr These findings provide the evidence that the combination of Mino and STAT3 inhibitor significantly decrease cell viability in vitro and in vivo It suggests that additional targeting STAT3 may provide an effective combination therapy for patients with malignant glioma

Date of Award	2016 Aug 11
Original language	English
Supervisor	Po-Wu Gean (Supervisor)