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

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JAŠKOVÁ Zuzana PAVLOVÁ Šárka MALČÍKOVÁ Jitka BRYCHTOVÁ Yvona TRBUŠEK Martin

Rok publikování 2020
Druh Článek v odborném periodiku
Časopis / Zdroj Leukemia Research
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub
Doi http://dx.doi.org/10.1016/j.leukres.2019.106288
Klíčová slova Chronic lymphocytic leukemia; TP53/p53; PRIMA-1(MET); Apoptosis
Popis 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.
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