Selective glucocorticoid receptor agonists as an alternative to glucocorticoids in the treatment of acute lymphoblastic leukemia: clinical response to glucocorticoids compared with molecular effects in vitro

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Abstract

Background. Glucocorticoids are widely used in the treatment of acute lymphoblastic leukemia. However, antileukemic effects are often accompanied by the development of serious metabolic and atrophic complications. A safer alternative may be drugs of the class of selective glucocorticoid receptor agonists with a more favorable safety profile.
Aim. To evaluate the effects of new selective glucocorticoid receptor agonists of the synephrine derivative class in vitro on bone marrow blasts of patients with acute lymphoblastic leukemia and compare the results with the clinical response to therapy.
Materials and methods. Bone marrow blasts of patients with acute lymphoblastic leukemia were isolated in a ficollurographin gradient. The proportion of viable cells was assessed using a resazurin test. The expression of specific glucocorticoid response marker genes was assessed using quantitative polymerase chain reaction. Therapeutic treatment response was assessed according to ALL IC-BFM 2009 protocol on 8, 15 and 33 days.
Results. IC50 values of novel selective glucocorticoid receptor agonists 10S-E2 and 13S-G2 were calculated with blasts death level in 50 %. The effects of the most cytotoxic compound 10S-E2 on the expression of glucocorticoid-regulated genes (FKBP51 and COX2), were evaluated and compared with clinical response to treatment.
Conclusion. The sensitivity of bone marrow leukemic blast cells to the 10S-E2 compound in vitro correlates with the clinical response of patients to glucocorticoid therapy, which suggests a good clinical response to therapy with potential drugs of selective glucocorticoid receptor agonists class.

About the authors

O. A. Vlasova

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Author for correspondence.
ORCID iD: 0000-0002-1498-849X

24 Kashirskoe Shosse, Moscow 115478 

Russian Federation

E. M. Zhidkova

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0003-3318-9391

24 Kashirskoe Shosse, Moscow 115478

Russian Federation

E. S. Lylova

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

24 Kashirskoe Shosse, Moscow 115478

Russian Federation

A. N. Demko

Ryazan State Medical University named after academician I.P. Pavlov, Ministry of Health of Russia

ORCID iD: 0000-0002-7941-5158

9 Vysokovoltnaya St., Ryazan 390026 

Russian Federation

M. G. Yakubovskaya

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia ; Peoples’ Friendship University of Russia

ORCID iD: 0000-0002-9710-8178

24 Kashirskoe Shosse, Moscow 115478

6 Miklukho-Maklaya St., Moscow 117198

Russian Federation

T. T. Valiev

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-1469-2365

24 Kashirskoe Shosse, Moscow 115478

Russian Federation

E. A. Lesovaya

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia ; Ryazan State Medical University named after academician I.P. Pavlov, Ministry of Health of Russia ; Peoples’ Friendship University of Russia

Email: lesovenok@yandex.ru
ORCID iD: 0000-0002-1967-9637

24 Kashirskoe Shosse, Moscow 115478

9 Vysokovoltnaya St., Ryazan 390026 

6 Miklukho-Maklaya St., Moscow 117198 

Russian Federation

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