Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide

Version 1 : Received: 22 December 2021 / Approved: 23 December 2021 / Online: 23 December 2021 (16:53:54 CET)

How to cite: Eda, T.; Okada, M.; Ogura, R.; Tsukamoto, Y.; Kanamaru, Y.; Watanabe, J.; On, J.; Aoki, H.; Oishi, M.; Takei, N.; Fujii, Y.; Natsumeda, M. Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide. Preprints 2021, 2021120396 (doi: 10.20944/preprints202112.0396.v1). Eda, T.; Okada, M.; Ogura, R.; Tsukamoto, Y.; Kanamaru, Y.; Watanabe, J.; On, J.; Aoki, H.; Oishi, M.; Takei, N.; Fujii, Y.; Natsumeda, M. Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide. Preprints 2021, 2021120396 (doi: 10.20944/preprints202112.0396.v1).

Abstract

Multimodal therapy including surgery, radiation treatment and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to exam-ine the signal activation patterns at GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose dependent manner. These effects of on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1) positive cells within the tumor. These results suggest that CLD suppresses GBM cell growth by the inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.

Keywords

glioblastoma; signal transduction; xenograft model; drug repositioning

Subject

MEDICINE & PHARMACOLOGY, Oncology & Oncogenics

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