New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration

Justyna Jakubowska,Katarzyna Kotulska,Bartłomiej Pawlik,Joanna Trelińska,Małgorzata Stolarska,Krystyna Wyka,Wojciech Młynarski,Sergiusz Jóźwiak

doi:10.3390/ijms22136802

Abstract

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 μM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 μM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.

Highlights

An important category of immunosuppressive and anticancer drugs is that of mammalian target of rapamycin inhibitors, i.e., rapamycin and their analogues everolimus, temisirolimus, and deforolimus
Until now, its most promising clinical application is in the treatment of tuberous sclerosis complex (TSC), a rare disease where a mutation of the TSC1 or TSC2 gene leads to overactivation of mTOR complex 1 (mTORC1), resulting in the growth of benign tumors in multiple organs including the brain, kidney, heart, and skin [7]
The mean corpuscular volume (MCV) value was significantly lower at all three time points compared to baseline: mean (95% CL) 79.47 fL (77.00–81.00 fL), 77.06 fL (74.00–79.00 fL), and 77.20 fL (74.00– 78.00 fL), for 3, 6, and 12 months, respectively, vs. 87.53 fL (86.00–90.00 fL), p < 10−5; it was found to be significantly lower at 6 months compared to 3 months (p = 0.00007)

Summary

Introduction

An important category of immunosuppressive and anticancer drugs is that of mammalian target of rapamycin (mTOR) inhibitors, i.e., rapamycin (sirolimus) and their analogues everolimus, temisirolimus, and deforolimus. This complex inhibits the mTOR regulatory protein kinase signal transduction pathway, which regulates cell growth, proliferation, and survival [1]. MTOR complex 1 (mTORC1) regulates translation and cell growth via phosphorylation of S6 kinase and eukaryotic initiation factor eIF4E binding protein (4E-BP) and is very sensitive to inhibition by rapamycin. The immunosuppressive properties of mTOR inhibitors allow them to be used in solid-organ transplantation to prevent acute rejection [2,3]. They possess antineoplastic activities, which provide effective treatment of many cancers (renal carcinoma, advanced breast cancer, neuroendocrine tumors of pancreatic origin) [4]. Until now, its most promising clinical application is in the treatment of tuberous sclerosis complex (TSC), a rare disease where a mutation of the TSC1 or TSC2 gene leads to overactivation of mTORC1, resulting in the growth of benign tumors in multiple organs including the brain, kidney, heart, and skin [7]

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