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Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma
Alyona Ivanova, Taylor M. Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das
Alyona Ivanova, Taylor M. Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das
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Research Article Cell biology Oncology

Lomitapide enhances cytotoxic effects of temozolomide in chemotherapy-resistant glioblastoma

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Abstract

More than a third of patients with glioblastoma experience tumor 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 in order 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 tumor recurrence in a mouse glioblastoma model, compared with treatment xwith TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.

Authors

Alyona Ivanova, Taylor M. Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das

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Figure 9

Lomitapide delays tumor recurrence and improves survival when combined with TMZ treatment in a glioblastoma xenograft model.

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Lomitapide delays tumor recurrence and improves survival when combined w...
After intracranial inoculation with luciferase-labeled CTL-U251 or TR-U251 cells, mice were randomized into 4 groups. Bioluminescent images were recorded using an IVIS Lumina II Bioluminescence System (PerkinElmer) every 7 days. Total photon flux values were quantified in tumor progression between treatment groups, as described in Sachdeva et al. 2019 (15). (A) Schematic showing in vivo experimental design for cells injected intracranially and thereafter treated with lomitapide, TMZ, or concomitant lomitapide and TMZ. (B) Bioluminescence imaging of intracranial glioblastoma mouse xenograft visualizing tumor growth of CTL-U251 cells. Empty spaces indicate sacrificed mice at humane endpoints. (C) Signal progression of total flux activity comparing tumor growth at 1- to 4-weeks after inoculation. (D) Total photon flux of concomitant TMZ and lomitapide-treated and TMZ alone–treated mice 1–4 weeks following transplantation. 2-tailed Student’s t test was used for statistical comparison between 2 groups. (E) Kaplan–Meier survival curves of mice injected with CTL-U251 in individual cohorts (n = 16). *P = 0.0239 for lomitapide + TMZ versus TMZ; **P = 0.0015 for lomitapide + TMZ versus lomitapide; **P = 0.013 for lomitapide + TMZ versus Control. (F) Kaplan–Meier survival curves of mice injected with TR-U251 in individual cohorts (n = 12). Median survival and statistical significance were determined by log-rank test corrected for multiple comparisons: ****P < 0.0001 for lomitapide + TMZ vs TMZ; P < 0.0001 for lomitapide + TMZ vs Control.

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