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Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide

Oxana Denisova; Anne Simonsen; Amra Grudic; Md Abdul Latif; Gro Vatne Røsland; Rolf Bjerkvig; Md Mahdi Hasan‐Olive; Tor‐Christian Johannessen; Morten Lund‐Johansen; Ning Yang; Jukka Westermarck; Bassam Janji; Karl Johan Tronstad; Anne Nordal; Jobin K. Varughese; Lars Prestegarden; Terje Sundstrøm; Halala Saed; Jian Wang; Huaiyang Zhu

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide

Oxana Denisova
Anne Simonsen
Amra Grudic
Md Abdul Latif
Gro Vatne Røsland
Rolf Bjerkvig
Md Mahdi Hasan‐Olive
Tor‐Christian Johannessen
Morten Lund‐Johansen
Ning Yang
Jukka Westermarck
Bassam Janji
Karl Johan Tronstad
Anne Nordal
Jobin K. Varughese
Lars Prestegarden
Terje Sundstrøm
Halala Saed
Jian Wang
Huaiyang Zhu
Katso/Avaa
Final draft (1.051Mb)
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Wiley-Liss Inc.
doi:10.1002/ijc.31912
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042827173
Tiivistelmä

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14–15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome‐wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late‐stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy‐lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.

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