Involvement of Signaling Cascades in Granulocytopoiesis Regulation under Conditions of Cytostatic Treatment
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 4, August, 2020
GENERAL PATHOLOGY AND PATHOPHYSIOLOGY Involvement of Signaling Cascades in Granulocytopoiesis Regulation under Conditions of Cytostatic Treatment
V. V. Zhdanov1,2, L. A. Miroshnichenko1, G. N. Zyuz’kov1, E. V. Udut1, T. Yu. Polyakova1, E. V. Simanina1, E. Yu. Sherstoboev1, L. A. Stavrova1, V. I. Agafonov1, M. Yu. Minakova1, A. V. Chaikovskii1, and A. M. Dygai1 Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 4, pp. 406-410, April, 2020 Original article submitted December 26, 2019 Suppression of the production of granulocytic CSF under the effect of 5-fluorouracyl is related to disorders in the NF-κB-, cAMP-dependent signaling pathways and MAPK cascade. These secondary messengers are involved in the regulation of functional activity of nonadherent myelokaryocytes starting from day 10 of the experiment (initial period of the hemopoietic granulocytic stem regeneration after antimetabolite challenge). Granulocytic CSF does not play essential role in the formation of colony-stimulating activity of cells of the adherent and nonadherent fractions of the bone marrow. Only cAMP-dependent pathway is involved in the regulation of the realization of the granulocytic precursor growth potential in response to the challenge. Key Words: NF-κB; p38; adenylate cyclase; myelosuppression; G-CSF Elements of the hemopoiesis-inducing microenvironment (HIM) play an important role in the maintenance of adequate hemopoiesis [1]. They determine the proliferative and differentiation status of hemopoietic precursor cells mainly by producing humoral regulators (cytokines and growth factors) via the cAMPdependent, MAP, and PI3K/Akt-signaling pathways [4-6,11-13]. The study of the role of signaling cascades in the hemopoiesis regulation processes under the effects of cytostatics is expected to extend our knowledge on the regularities of hemopoietic tissue response to challenge and to promote the development of new pathogenetically-substantiated methods for drug correction of hypoplastic conditions [3,14]. In turn, various antiblastoma drugs produce different E. D. Goldberg Research Institute of Pharmacology and Rege nerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences; 2National Research Tomsk State University, Tomsk, Russia. Address for correspondence: [email protected]. L. A. Miroshnichenko 1
effects on HIM elements [6-10], which suggests different changes in some signaling intracellular pathways under conditions of cytostatic treatment. Here we studied the role of NF-κB- and cAMPdependent signaling pathways and MAPK cascade in the regulation of granulocytopoiesis suppressed by 5-fluorouracyl (5-FU).
MATERIALS AND METHODS The study was carried out on certified male C57BL/6 mice (n=64; 20-22 g; age 2 months) from the Department of Experimental Biomodels, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine. Experimental mice received a single intraperitoneal injection of 5-
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