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® ), 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 IC50 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.

• Authors: Kenta Kuramoto, Masahiro Yamamoto, Shuhei Suzuki, Tomomi Sanomachi, Keita Togashi, Shizuka Seino, Chifumi Kitanaka, Masashi Okada
• Journal: The FEBS journal (FEBS J) Vol. 287 Issue 10 Pg. 2023-2036 (05 2020) ISSN: 1742-4658 [Electronic] England
• PMID: 31868973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Federation of European Biochemical Societies.

Chemical References

• Antineoplastic Agents
• Verteporfin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Mice
• Neoplastic Stem Cells (drug effects)
• Oxidative Phosphorylation (drug effects)
• Verteporfin (pharmacology)
• Xenograft Model Antitumor Assays