PRIMA-1MET cytotoxic effect correlates with p53 protein
reduction in TP53-mutated chronic lymphocytic leukemia cells

J 2020

PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells

JAŠKOVÁ, Zuzana, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Yvona BRYCHTOVÁ, Martin TRBUŠEK et. al.

Základní údaje

Originální název

PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells

Autoři

JAŠKOVÁ, Zuzana (703 Slovensko, domácí), Šárka PAVLOVÁ (203 Česká republika, domácí), Jitka MALČÍKOVÁ (203 Česká republika, domácí), Yvona BRYCHTOVÁ (203 Česká republika, domácí) a Martin TRBUŠEK (203 Česká republika, garant, domácí)

Vydání

Leukemia Research, Oxford, Pergamon Press, 2020, 0145-2126

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30205 Hematology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.156

Kód RIV

RIV/00216224:14110/20:00115275

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1016/j.leukres.2019.106288

UT WoS

000509785500002

Klíčová slova anglicky

Chronic lymphocytic leukemia; TP53/p53; PRIMA-1(MET); Apoptosis

Štítky

14110212, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 9. 11. 2020 10:55, Mgr. Tereza Miškechová

Anotace

V originále

TP53 gene defects represent the most unfavorable prognostic factor in chronic lymphocytic leukemia (CLL). Although recently introduced small-molecule B-cell receptor signalling inhibitors have revolutionized CLL treatment, data for ibrutinib still point to impaired prognosis for TP53-affected patients. Among cancer-associated TP53 mutations, missense substitutions predominate and typically result in a high mutated-p53 protein level. Therefore, rescuing the p53 tumor suppressor function through specific small molecules restoring p53 wild-type (wt) conformation represents an attractive therapeutic strategy for cancer patients with TP53 missense mutations. We tested the effect of mutated-p53 reactivating molecule PRIMA-1(MET) in 62 clinical CLL samples characterized for TP53 mutations and p53 protein level. At the subtle PRIMA-1(MET) concentrations (1-4 mu M), most samples manifested concentration-dependent viability decrease and, conversely, apoptosis induction, with the response being similar in both the TP53-mutated and TP53-wt groups, as well as in the TP53-mutated samples with p53 protein stabilization and without it. PRIMA-1(MET) was able to reduce mutated p53 protein in a proportion of TP53-mutated CLL samples, and this reduction correlated with a significantly stronger viability decrease and apoptosis induction than samples with stable p53 levels. CLL cells are mostly sensitive to PRIMA-1(MET) apart from those with stable mutated p53.

Návaznosti

MUNI/A/1105/2018, interní kód MU

Název: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VI (Akronym: VýDiTeHeMA VI)

Investor: Masarykova univerzita, Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VI, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

Citovat

JAŠKOVÁ, Zuzana, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Yvona BRYCHTOVÁ a Martin TRBUŠEK. PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells. Leukemia Research. Oxford: Pergamon Press, 2020, roč. 89, FEB 2020, s. 1-7. ISSN 0145-2126. Dostupné z: https://dx.doi.org/10.1016/j.leukres.2019.106288.

@article{1614689,
   author = {Jašková, Zuzana and Pavlová, Šárka and Malčíková, Jitka and Brychtová, Yvona and Trbušek, Martin},
   article_location = {Oxford},
   article_number = {FEB 2020},
   doi = {http://dx.doi.org/10.1016/j.leukres.2019.106288},
   keywords = {Chronic lymphocytic leukemia; TP53/p53; PRIMA-1(MET); Apoptosis},
   language = {eng},
   issn = {0145-2126},
   journal = {Leukemia Research},
   title = {PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells},
   url = {https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub},
   volume = {89},
   year = {2020}
}

TY  - JOUR
ID  - 1614689
AU  - Jašková, Zuzana - Pavlová, Šárka - Malčíková, Jitka - Brychtová, Yvona - Trbušek, Martin
PY  - 2020
TI  - PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells
JF  - Leukemia Research
VL  - 89
IS  - FEB 2020
SP  - 1-7
EP  - 1-7
PB  - Pergamon Press
SN  - 01452126
KW  - Chronic lymphocytic leukemia
KW  - TP53/p53
KW  - PRIMA-1(MET)
KW  - Apoptosis
UR  - https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub
L2  - https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub
N2  - TP53 gene defects represent the most unfavorable prognostic factor in chronic lymphocytic leukemia (CLL). Although recently introduced small-molecule B-cell receptor signalling inhibitors have revolutionized CLL treatment, data for ibrutinib still point to impaired prognosis for TP53-affected patients. Among cancer-associated TP53 mutations, missense substitutions predominate and typically result in a high mutated-p53 protein level. Therefore, rescuing the p53 tumor suppressor function through specific small molecules restoring p53 wild-type (wt) conformation represents an attractive therapeutic strategy for cancer patients with TP53 missense mutations. We tested the effect of mutated-p53 reactivating molecule PRIMA-1(MET) in 62 clinical CLL samples characterized for TP53 mutations and p53 protein level. At the subtle PRIMA-1(MET) concentrations (1-4 mu M), most samples manifested concentration-dependent viability decrease and, conversely, apoptosis induction, with the response being similar in both the TP53-mutated and TP53-wt groups, as well as in the TP53-mutated samples with p53 protein stabilization and without it. PRIMA-1(MET) was able to reduce mutated p53 protein in a proportion of TP53-mutated CLL samples, and this reduction correlated with a significantly stronger viability decrease and apoptosis induction than samples with stable p53 levels. CLL cells are mostly sensitive to PRIMA-1(MET) apart from those with stable mutated p53.
ER  -

JAŠKOVÁ, Zuzana, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Yvona BRYCHTOVÁ a Martin TRBUŠEK. PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells. \textit{Leukemia Research}. Oxford: Pergamon Press, 2020, roč.~89, FEB 2020, s.~1-7. ISSN~0145-2126. Dostupné z: https://dx.doi.org/10.1016/j.leukres.2019.106288.

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