Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma

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Abstract
More than one third of patients with glioblastoma experience tumour progression during adjuvant therapy. In this study, we performed a high-throughput drug repurposing screen of FDA-approved agents capable of crossing the blood-brain barrier that to find agents to counteract acquired or inherent glioma cell resistance to temozolomide-associated cytotoxicity. We identified the cholesterol processing inhibitor, lomitapide, as a potential chemosensitizer in glioblastoma. In vitro treatment of temozolomide-resistant glioblastoma cells with lomitapide resulted in decreased intracellular ubiquinone levels and sensitized cells to temozolomide-induced ferroptosis. Concomitant treatment with lomitapide and temozolomide (TMZ) prolonged survival and delayed tumour recurrence in a mouse glioblastoma model, compared to treatment with TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.
Funding Information
  • Oxford University Press (Synaptive, VPiX, royalties)
  • Canadian Institutes of Health Research (CIHR-OG-341329)
  • Meagan’s Walk (Meagan’s Walk)
  • Brainchild (Brainchild)
  • the Early Research Award from the Province of Ontario (the Early Research Award from the Province of Ontario)
  • Keenan Chair in Surgery (Keenan Chair in Surgery)
  • Gratitude 10 (philanthropic funds)
  • Calum Macbeth Fund (Calum Macbeth Fund)
  • Ontario Graduate Scholarship (OGS)
  • Oxford University Press (Synaptive, VPiX, royalties)

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