Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells

Abstractp53 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- 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 leukaemia 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 leukaemias withwtTP53.

B-cell chronic lymphocytic leukaemia in an African lion (Panthera leo)

A 15-year-old female African lion (Panthera leo) maintained at the Zoological Garden of Pistoia, Tuscany (Italy), showed signs of malaise, dyspnoea, tremors, pale mucous membranes and ataxia for two days prior to death. Complete blood count showed anaemia, thrombocytopaenia and severe lymphocytosis. At autopsy, the most relevant finding was severe, generalised splenomegaly. Histologically, high numbers of neoplastic lymphocytes diffusely infiltrated the spleen, liver, heart, pancreas, kidney and lungs. The lymphoid cells were positive for CD79a and negative for CD3 on immunohistochemistry. The histologic features of the neoplastic cells and their immunophenotype are consistent with B-cell lymphocytes. Based on surface membrane co-expression of immunoglobulin M and immunoglobulin D in most neoplastic cells, which indicated that they were naïve, antigen-inexperienced and mature circulating resting B-cells, and consistent with their appearance as small lymphocytes with high nuclear-to-cytoplasmic ratios, a diagnosis of B-cell chronic lymphocytic leukaemia was made.