Substrate Affinity Is Not Crucial for Therapeutic L-Asparaginases: Antileukemic Activity of Novel Bacterial Enzymes.

Autor: Ściuk A; Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, 30-348 Krakow, Poland.; II Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland., Wątor K; Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.; II Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland., Staroń I; Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.; II Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland., Worsztynowicz P; Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland., Pokrywka K; Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland., Sliwiak J; Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland., Kilichowska M; Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, 30-348 Krakow, Poland., Pietruszewska K; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland., Mazurek Z; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland., Skalniak A; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland., Lewandowski K; Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Szamarzewskiego 84, 60-569 Poznan, Poland., Jaskolski M; Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.; Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznanskiego 8, 61-614 Poznan, Poland., Loch JI; Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland., Surmiak M; II Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland.; Center for the Development of Therapies for Civilization and Age-Related Diseases, Jagiellonian University Medical College, Skawińska 8, 31-066 Krakow, Poland.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2024 May 11; Vol. 29 (10). Date of Electronic Publication: 2024 May 11.
DOI: 10.3390/molecules29102272
Abstrakt: L-asparaginases are used in the treatment of acute lymphoblastic leukemia. The aim of this work was to compare the antiproliferative potential and proapoptotic properties of novel L-asparaginases from different structural classes, viz. EcAIII and KpAIII (class 2), as well as ReAIV and ReAV (class 3). The EcAII (class 1) enzyme served as a reference. The proapoptotic and antiproliferative effects were tested using four human leukemia cell models: MOLT-4, RAJI, THP-1, and HL-60. The antiproliferative assay with the MOLT-4 cell line indicated the inhibitory properties of all tested L-asparaginases. The results from the THP-1 cell models showed a similar antiproliferative effect in the presence of EcAII, EcAIII, and KpAIII. In the case of HL-60 cells, the inhibition of proliferation was observed in the presence of EcAII and KpAIII, whereas the proliferation of RAJI cells was inhibited only by EcAII. The results of the proapoptotic assays showed individual effects of the enzymes toward specific cell lines, suggesting a selective (time-dependent and dose-dependent) action of the tested L-asparaginases. We have, thus, demonstrated that novel L-asparaginases, with a lower substrate affinity than EcAII, also exhibit significant antileukemic properties in vitro, which makes them interesting new drug candidates for the treatment of hematological malignancies. For all enzymes, the kinetic parameters (K m and k cat ) and thermal stability (T m ) were determined. Structural and catalytic properties of L-asparaginases from different classes are also summarized.
Databáze: MEDLINE
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