| Author | Ochioni, Alan C. | |
| Author | Imbroisi Filho, Ricardo | |
| Author | Esteves, Amanda M. | |
| Author | Leandro, João G.B. | |
| Author | Demaria, Thainá M. | |
| Author | Nascimento Junior, Jose Xavier do | |
| Author | Dutra, Filipe S. Pereira | |
| Author | Bozza, Patrícia T. | |
| Author | Sola-Penna, Mauro | |
| Author | Zancan, Patricia | |
| Access date | 2021-11-06T20:32:30Z | |
| Available date | 2021-11-06T20:32:30Z | |
| Document date | 2021 | |
| Citation | OCHIONI, Alan C. et al. Clotrimazole presents anticancer properties against a mouse melanoma model acting as a PI3K inhibitor and inducing repolarization of tumor-associated macrophages. BBA-Molecular Basis of Disease, n. 1867, 166263, p. 1-10, Sept. 2021. | pt_BR |
| ISSN | 0925-4439 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/49717 | |
| Language | eng | pt_BR |
| Publisher | Elsevier | pt_BR |
| Rights | restricted access | |
| Subject in Portuguese | Câncer | pt_BR |
| Subject in Portuguese | Inflamação | pt_BR |
| Subject in Portuguese | Lactato | pt_BR |
| Subject in Portuguese | Via PI3K | pt_BR |
| Subject in Portuguese | Citotoxicidade | pt_BR |
| Subject in Portuguese | Macrófagos associados a tumor | pt_BR |
| Title | Clotrimazole presents anticancer properties against a mouse melanoma model acting as a PI3K inhibitor and inducing repolarization of tumor-associated macrophages | pt_BR |
| Type | Article | |
| DOI | 10.1016/j.bbadis.2021.166263 | |
| Abstract | The immune system is a key component of tumorigenesis, with the latter promoting the development of cancer,
its progression and metastasis. In fact, abundant infiltration of tumor-associated macrophages (TAM), which are
M2-like macrophages, has been associated with a poor outcome in most types of cancers. Here, we show that
lactate produced by murine melanoma B16F10 cells induces an M2-like profile in cultured macrophages. Further,
we demonstrate that clotrimazole (CTZ), an off-target anti-tumor drug, abolishes lactate effects on the activation
of macrophages and induces the expression of M1-like markers. We show that clotrimazole has cytotoxic effects
on tumor cells by negatively modulating PI3K, which inhibits glycolytic metabolism and leads to a diminishing
lactate production by these cells. These effects are more pronounced in cancer cells exposed to conditioned media
of M2-polarized macrophages. Moreover, clotrimazole inhibits tumor growth in a murine model of implanted
melanoma, reduces lactate content in a tumor microenvironment and decreases vascular endothelial growth
factor expression. Finally, clotrimazole drastically diminishes TAM infiltration in the tumors, thereby inducing
M1 polarization. Collectively, these findings identify a new antitumor mechanism of clotrimazole by modulating
the tumor microenvironment (TME), particularly the activation and viability of TAM. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Oncobiologia Molecular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Oncobiologia Molecular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Oncobiologia Molecular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Enzimologia e Controle do Metabolismo. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Enzimologia e Controle do Metabolismo. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Oncobiologia Molecular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Enzimologia e Controle do Metabolismo. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Biotecnologia Farmacêutica. Laboratório de Oncobiologia Molecular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Cancer | pt_BR |
| Subject | Inflammation | pt_BR |
| Subject | Lactate | pt_BR |
| Subject | PI3K pathway | pt_BR |
| Subject | Cytotoxicity | pt_BR |
| Subject | TAMs | pt_BR |
| Embargo date | 2023 | |
