Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Abstract

Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

“…We searched for a drug exhibiting GSC-selective cytotoxic effects using GSCs and, as a control, genetically identical (isogenic) differentiated GSCs (differentiated GSCs) acquired through the induction of differentiation of GSCs. As a result, we identified several candidate GSC-selective cytotoxic drugs [ 7 , 8 ], one being methotrexate (MTX). MTX is a folate antagonist currently employed as a therapeutic drug for rheumatism, which also has a long history of use as an antitumor drug to mainly treat malignant lymphoma [ 9 , 10 , 11 ].…”

“…Using the drug repositioning/repurposing technique, we discovered a number of inducers of GSC differentiation [ 2 , 3 , 4 ]. With a goal of reducing residual GSCs after differentiation therapies, we searched for GSC-killing drugs using a similar approach and identified a number of drugs that selectively inhibit the survival of GSCs, among which were inhibitors of oxidative phosphorylation, which is more strongly activated in GSCs than in non-GSCs [ 7 , 8 ]. Of note, among these GSC-selective cytotoxic drugs were folate antagonists.…”

The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor

“…Kuramoto et al found that VP reduced oxidative phosphorylation in glioma stem cells (GSCs) and decreased mitochondrial membrane potential (MMP) and ATP levels, leading to massive GSCs death. Furthermore, the cytotoxic effect of VP was specific to the GSCs, rather than normal human fibroblasts, mouse astrocytes or rat neural stem cells,independent of YAP and ROS (Kuramoto et al, 2019). To summarize, repositioned VP can also regulate the AKT/mTOR, IL-6/STAT3 and FAK signaling pathways, and inhibit CSCs partially independent of YAP.…”

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

“…It inhibits OXPHOS at complex III and IV and is specifically effective against GSCs and not to differentiated glioblastoma cells or normal cells. 214 Recently, verteporfin was suggested to be a therapeutic agent for epidermal growth factor receptor (EGFR)-amplified and EGFR-mutant glioblastoma on the basis of a study using cultured glioblastoma cells. 215 The FDA-approved antidiabetic drug metformin and the FDA-approved antimalaria drug chloroquine have been tested in a phase IB clinical trial to investigate whether repurposing of these drugs can optimize standard treatment of IDH1-mutated glioblastoma and other IDH1-mutated cancer types, but failed to induce a clinical response.…”