Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity

Abstract

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma

“…We have previously shown in healthy rats [ 16 ] and mice [ 12 ] that bortezomib induced LV systolic dysfunction that was most pronounced after the first doses of the drug and gradually resolved both with continuation of therapy and after its discontinuation [ 16 ]. Moreover, it was rather mild and of unlikely clinical significance in a healthy subject.…”

“…Since we have already shown that MM is characterized by increased arginase activity [ 12 ] and ʟ-arginine is an essential substrate for NO production [ 30 ], we tested if an arginase inhibitor improves NO-mediated endothelial function through preservation of ʟ-arginine supply for NO synthesis. However, OAT-1746 only mildly increased plasma nitrite concentrations in healthy and MM mice, slightly improved endothelial function in healthy mice (only bradykinin response), and even tended to reduce it in MM animals.…”

“…Improvement of cardiomyocyte calcium handling [ 32 ] and reduction of apoptosis and inflammation [ 33 ] are other potential mechanisms of beneficial effects of arginase inhibition on cardiac function. We have previously shown that another arginase inhibitor, INCB01158, protected mice from bortezomib-induced cardiotoxicity [ 12 ], while sildenafil, a phosphodiesterase-5 inhibitor that reduced degradation of cGMP, an intracellular second messenger of NO, protected bortezomib-treated healthy rats from LV dysfunction [ 12 ]. This indicates that the NO pathway, in general, is a promising target for the reduction of MM- and PI-related cardiotoxicity.…”

“…Since we have already shown that MM is characterized by increased arginase activity [12] eloma is a hematological malignancy associated with increased ortality. Its therapies also result in adverse cardiac effects.…”

“…Experimental studies indicate that increased plasma viscosity results in increased NO synthesis [ 10 ] through stimulation of endothelial nitric oxide (NO) synthase [ 11 ]. On the other hand, we have shown that in the mouse model of non-light chain MM, systemic concentrations of ʟ-arginine, a precursor for NO synthesis, are progressively reduced, correlating with arginase expression in myeloid cells [ 12 ]. Therefore, the effects of MM on endothelial function and systemic NO availability remain unknown.…”