Changes in the expression of genes that regulate apoptosis as a factor in the development of chemoresistance in soft tissue sarcoma

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Abstract

Introduction. The active use of highly toxic chemotherapy in the treatment of soft tissue sarcomas determines the need to search for criteria and markers of chemoresistance of patients to the therapy.
Aim. To study the connection between tumor cell resistance to chemotherapy and expression levels of apoptosis-regulating proteins (PUMA, PMAIP-1, PIDD-1, AIFM-2, Bax, GADD45a) in primary cultures of soft tissue sarcomas.
Materials and methods. Primary cultures of soft tissue sarcomas were obtained using enzymatic digestion, cell death was evaluated using resazurine assay. Gene expression was measured using real-time polymerase chain reaction, protein levels using immunoblotting assay.
Results. 73 primary cultures of soft tissue sarcomas were obtained, for which chemosensitivity to doxorubicin, ifosfamide, docetaxel, gemcitabine, pazopanib and their combinations was determined using a resazurin cytotoxicity test. Associations of AIFM-2 gene expression with resistance to pazopanib, doxorubicin and its combination with ifosfamide were found in liposarcoma, synovial and undifferentiated pleomorphic sarcomas. In addition, associations between the expression of the Bax, PUMA, PMAIP-1, GADD45a and PIDD-1 genes and resistance to the studied drugs in various nosological subgroups of sarcomas were identified. When studying the amount of protein, it was revealed that undifferentiated pleomorphic and synovial sarcomas with a low content of GADD45a are more resistant to the studied drugs. Liposarcomas with high Bax expression are more resistant to docetaxel and gemcitabine, while synovial sarcomas with high Bax expression are more sensitive to doxorubicin and ifosfamide.
Conclusion. The data obtained indicate a relationship between the activity of the studied genes-regulators of apoptosis and resistance to drugs used in the treatment of soft tissue sarcomas.

About the authors

T. I. Fetisov

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

Author for correspondence.
Email: TimkaTryam@yandex.ru
ORCID iD: 0000-0002-5082-9883

Timur Igorevich Fetisov

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

S. A. Khazanova

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-8350-0021

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

P. A. Shtompel

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

Email: fake@neicon.ru
ORCID iD: 0009-0000-8673-597X

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

E. S. Trapeznikova

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

Email: fake@neicon.ru
ORCID iD: 0000-0001-6839-7436

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

A. A. Tararykova

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-5548-3295

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

V. Yu. Zinovyeva

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

Email: fake@neicon.ru

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

V. I. Marshall

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-0081-2688

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

A. A. Lowenger

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

Email: fake@neicon.ru
ORCID iD: 0009-0000-3317-9543

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

I. S. Kupaeva

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

Email: fake@neicon.ru
ORCID iD: 0000-0003-4229-5911

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

D. V. Rogozhin

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

Email: fake@neicon.ru
ORCID iD: 0000-0003-0777-9152

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

A. Yu. Bokhyan

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-1396-3434

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

G. A. Belitsky

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-3167-7204

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

M. G. Yakubovskaya

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-9710-8178

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

K. I. Kirsanov

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

Email: fake@neicon.ru
ORCID iD: 0000-0002-8599-6833

24 Kashirskoe Shosse, Moscow 115522

6 Miklukho-Maklaya St., Moscow 117198

Russian Federation

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