Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity.

BACKGROUND: Immune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1-dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to MOs (monocytes) activity during their crosstalk with breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities, including cellular immunometabolism and protective redox signaling based-biomarkers, intracellular free calcium ions (ifCa2+), phagocytosis and co-operative cytokines (IFN-γ and IL-10) of autologous MOs before and during their interplay with primary ER-/PR-/HER2+ breast cancer cells. METHODS: Human primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET. RESULTS: MET downregulated breast cancer cell proliferation and phagocytosis, while having no significant effect on the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, we observed that, in the absence of MET treatment, the levels of lactate dehydrogenase (LDH)-based cytotoxicity, catalase, ifCa2+, IL-10 and arginase activity were significantly reduced in co-cultures compared to levels in MOs cultured alone whereas levels of inducible nitric oxide synthase (iNOS) activity were significantly increased. In contrast, MET treatment reduced the effects measured in co-culture on the levels of LDH-based cytotoxicity, arginase activity, catalase, ifCa2+, and IFN-γ. MET also induced upregulation of both iNOS and arginase in MO cells, although the increase did not reach significant difference for iNOS activity. Moreover, MET induced a robust increase of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. Furthermore, MET markedly upregulated the levels of IFN-γ production and downregulated those of IL-10 in isolated MOs, while inducing a slight opposing up-regulation of IL-10 production in co-cultures. CONCLUSIONS: Our results show that the biomarkers of phenotypic functional activities of MOs are modified after co-culturing with primary human breast cancer cells. Treatment of co-cultures with MET resulted in increased release of antitumor cytokine IFN-γ and ifCa2+, and increased cell necrosis during breast cancer cells-MOs crosstalk.

Aspirin enhances regulatory functional activities of monocytes and downregulates CD16 and CD40 expression in myocardial infarction autoinflammatory disease.

BACKGROUND: Exacerbation of CD16 as molecule marker of both intermediate and non-classical monocytes (MOs) has been shown to be involved in the pathogenesis of myocardial infarction (MI). In this study, we have tried to evaluate the aspirin (acetylsalicylic acid, ASA) treatment effect on the CD16-expressed MOs and activation-associated CD40 in MI. METHODS: MOs were isolated from the whole blood of healthy controls and patients with MI. The cells were stimulated and treated with different doses of ASA. RESULTS: ASA significantly decreased nitric oxide (NO) production and inducible NO synthase (iNOS) activity, but significantly increased arginase activity. Levels of interleukin (IL)-1ß, IL-6 and interferon-γ (IFN-γ) were downregulated, whereas those of IL-10 were upregulated. Additionally, ASA induced a markedly increase in both phagocytosis and intracellular pathogen killing activities. Moreover, ASA treatment induced significantly upregulation of intracellular levels of glucose (iGlu), and free calcium ions (ifCa2+), and, covertly, significantly downregulation of total cellular cholesterol content (tccCHOL). Furthermore, the expression levels of CD16 and CD40 were significantly downregulated in ASA-treated MOs. CONCLUSIONS: We show for the first time that ASA immunomodulates the functional activities of MOs during MI and promotes their switching toward a classical phenotype, exhibiting low CD16 expression levels and thereby anti-inflammatory properties.