Abstract
p53 is a tumor suppressor, which belongs to the p53 family of proteins. The family consists of p53, p63 and p73 proteins, which share similar structure and function. Activation of wild-type p53 or TAp73 in tumors leads to tumor regression, and small molecules restoring the p53 pathway are in clinical development. Protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid, is a clinically approved drug applied in photodynamic diagnosis and therapy. PpIX induces p53-dependent and TAp73-dependent apoptosis and inhibits TAp73/MDM2 and TAp73/MDM4 interactions. Here we demonstrate that PpIX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and activates apoptosis in B-cell chronic lymphocytic leukemia cells without illumination and without affecting normal cells. PpIX stabilizes p53 and TAp73 proteins, induces p53-downstream apoptotic targets and provokes cancer cell death at doses non-toxic to normal cells. Our findings open up new opportunities for repurposing PpIX for treating lymphoblastic leukemia with wild-type TP53.
Highlights
B-cell chronic lymphocytic leukemia (CLL) is one of the most common forms of blood cancers[1,2]
We demonstrate that Protoporphyrin IX (PpIX) triggers accumulation of p53 and TAp73 and activates cell death at doses not affecting healthy peripheral blood mononuclear cells (PBMCs)
It has been previously shown that PpIX inhibits p53/ MDM2 interactions, induces p53-dependent reporter and apoptosis in human cancer cells expressing wild-type p5335,36
Summary
B-cell chronic lymphocytic leukemia (CLL) is one of the most common forms of blood cancers[1,2]. In patients over the age of 80 years, the incidence increases to greater than 30/100 000 per year. CLL develops mostly in patients above the age of 72 years old which is linked to poor prognosis[3]. Com) 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, 171 65 Stockholm, Sweden 2Department of Immunology, Genetics and Pathology, Medical Faculty, Uppsala University, Box 25675105 Uppsala, Sweden Full list of author information is available at the end of the article. These authors contributed : Liren Jiang, Natasha Malik, Pilar Acedo Edited by I. Harris than women and leukemia incidence in both genders increases above the age of 554
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