Clotrimazole reverses macrophage M2 polarization by disrupting the PI3K/AKT/mTOR pathway

Abstract

Macrophages switch among different activation phenotypes according to distinct environmental stimuli, varying from pro-inflammatory (M1) to alternative (also named resolutive; M2) activation forms. M1-and M2-activated macrophages represent the two extremes of the activation spectrum involving multiple species, which vary in terms of function and the cytokines secreted. The consensus is that molecular characterization of the distinct macrophage population and the signals driving their activation will help in explaining disease etiology and formulating therapies. For instance, myeloid cells residing in the tumor microenvironment are key players in tumor progression and usually display an M2-like phenotype, which help tumor cells to evade local inflammatory processes. Therefore, these specific cells have been proposed as targets for tumor therapies by changing their activation profile. Furthermore, M2 polarized macrophages are phagocytic cells promoting tissue repair and wound healing and are therefore potential targets to treat different diseases. We have already shown that clotrimazole (CTZ) decreases tumor cell viability and thus tumor growth. The mechanism by which CTZ exerts its effects remains to be determined, but this drug is an inhibitor of the PI3K/AKT/mTOR pathway. In this study, we show that CTZ downregulated M2-activation markers in macrophages polarized to the M2 profile. This effect occurred without interfering with the expression of M1-polarized markers or pro-inflammatory cytokines and signaling. Moreover, CTZ suppressed NFkB pathway intermediates and disrupted PI3K/AKT/mTOR signaling. We concluded that CTZ reverses macrophage M2 polarization by disrupting the PI3K/AKT/mTOR pathway, which results in the suppression of NFkB induction of M2 polarization. In addition, we find that CTZ represents a promising therapeutic tool as an antitumor agent.