Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells

Abstract

Glioblastoma is the most common and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas, but it is not curative. The difficulties in treating glioblastoma may be as a result of the presence of glioma stem cells (GSCs), which are a source of relapse and chemoresistance. Another reason may be that endogenous Akt kinase activity may be activated in response to clinically relevant concentrations of TMZ. Akt activation is correlated with the increased tumorigenicity, invasiveness and stemness of cancer cells and overexpression of an active form of Akt increases glioma cell resistance to TMZ. Mounting evidence has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of Akt and down-regulation of the PI3K/Akt pathway may enhance the cytotoxicity of TMZ. Metformin (MET), the first-line drug for treating diabetes, it has been proved that it reduces AKT activation and selectively kills cancer stem cells, but whether it can potentiate the cytotoxicity of TMZ for GSCs remains unknown. In the present study, the GSCs isolated from human glioma cell line U87 and Rat glioma cell line C6, in vitro treatment with TMZ either alone or with MET. The present study demonstrates that MET acts synergistically with TMZ in inhibiting GSCs proliferation and generating the highest apoptotic rates when compared to either drug alone. These findings implicate that GSCs cytotoxicity mediated by TMZ may be stimulated by MET, have a synergistic effect, but the definite mechanisms remain elusive.

PLK1 inhibitor facilitates the suppressing effect of temozolomide on human brain glioma stem cells

“…Glioblastoma has been classified as the highest grade glioma (grade IV) by the WHO . Glioblastoma is the most irresistible malignant brain cancer in adults . The recurrence rate is very high with a median survival of 14.6 months despite aggressive multimodal therapy .…”

Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2

“…14 In addition to its blood glucose-lowering effect, metformin may also exert antineoplastic effects. 15 In glioma, metformin has been shown to inhibit proliferation [16][17][18][19][20] and invasion, 21 to induce apoptosis, 16,18,19 autophagy 18 and differentiation of BTICs, 22 and to increase radio-or chemosensitivity, 18,19,23,24 while leaving mature neurons largely unaffected. 25 Metformin mainly acts by inhibition of complex-I of the respiratory chain, 26 thereby leading to altered AMPK and mTOR-signaling.…”

Metformin treatment reduces temozolomide resistance of glioblastoma cells

“…In addition, metformin might have synergistic effects with TMZ treatment and enhance chemotherapy efficacy in GBM [15–17], which opens a new avenue to overcome TMZ resistance in glioma treatment. As an inexpensive, well-tolerated, first-line anti-diabetic oral drug, metformin has been reported to significantly reduce gluconeogenesis in the liver and increase insulin receptor sensitivity and glucose uptake in peripheral tissues.…”