Clotrimazole presents anticancer properties against a mouse melanoma model acting as a PI3K inhibitor and inducing repolarization of tumor-associated macrophages

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1867; no. 12; p. 166263
• Main Authors: Ochioni, Alan C, Imbroisi Filho, Ricardo, Esteves, Amanda M, Leandro, João G B, Demaria, Thainá M, do Nascimento Júnior, José Xavier, Pereira-Dutra, Filipe S, Bozza, Patricia T, Sola-Penna, Mauro, Zancan, Patricia
• Format: Journal Article
• Language: English
• Published: Netherlands 01-12-2021
• Subjects: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Polarity - drug effects; Cell Proliferation - drug effects; Clotrimazole - pharmacology; Humans; Melanoma, Experimental - drug therapy; Melanoma, Experimental - genetics; Melanoma, Experimental - pathology; Mice; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - genetics; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Tumor Microenvironment - drug effects; Tumor-Associated Macrophages - drug effects; Cytotoxicity; PI3K pathway; Inflammation; Lactate; TAMs; Cancer
• ISSN: 1879-260X
• DOI: 10.1016/j.bbadis.2021.166263

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.