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2023
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- IOC - Artigos de Periódicos [12973]
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CLOTRIMAZOLE PRESENTS ANTICANCER PROPERTIES AGAINST A MOUSE MELANOMA MODEL ACTING AS A PI3K INHIBITOR AND INDUCING REPOLARIZATION OF TUMOR-ASSOCIATED MACROPHAGES
Inflamação
Lactato
Via PI3K
Citotoxicidade
Macrófagos associados a tumor
Author
Affilliation
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.
Keywords in Portuguese
CâncerInflamação
Lactato
Via PI3K
Citotoxicidade
Macrófagos associados a tumor
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