Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia

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Rinne, Maiju and Mätlik, Kert and Ahonen, Tiina and Vedovi, Fabio and Zappia, Giovanni and Moreira, Vania and Yli-Kauhaluoma, Jari and Leino, Sakari and Salminen, Outi and Kalso, Eija and Airavaara, Mikko and Xhaard, Henri (2020) Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia. European Journal of Pharmaceutical Sciences, 154. 105493. ISSN 0928-0987 (https://doi.org/10.1016/j.ejps.2020.105493)

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Abstract

Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα production was not mediated through cytotoxity at ≤ 1 µM concentration for pixantrone and mitoxantrone (2-hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.

ORCID iDs

Rinne, Maiju, Mätlik, Kert, Ahonen, Tiina, Vedovi, Fabio, Zappia, Giovanni, Moreira, Vania ORCID logoORCID: https://orcid.org/0000-0001-6169-5035, Yli-Kauhaluoma, Jari, Leino, Sakari, Salminen, Outi, Kalso, Eija, Airavaara, Mikko and Xhaard, Henri;
CORE (COnnecting REpositories)