Pharmacological activation of the p53 pathway in haematological malignancies

Abstract

p53 gene mutations are rarely detected at diagnosis in common haematological cancers such as multiple myeloma (MM), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and Hodgkin's disease (HD), although their prevalence may increase with progression to more aggressive or advanced stages. Therapeutic induction of p53 might therefore be particularly suitable for the treatment of haematological malignancies. Some of the anti-tumour activity of current chemotherapeutics has been derived from activation of p53. However, until recently it was unknown whether p53 signalling is functional in certain haematological cancers including MM and if p53 activity is sufficient to trigger an apoptotic response. With the recent discovery of nutlins, which represent the first highly selective small molecule inhibitors of the p53-MDM2 interaction, pharmacological tools are now available to induce p53 irrespective of upstream signalling defects, and to functionally analyse the downstream p53 pathway in primary leukaemia and lymphoma cells. Combination therapy is emerging as a key factor, and development of non-genotoxic combinations seems very promising for tackling the problems of toxicity and resistance. This review will highlight recent findings in the research into molecules capable of modulating p53 protein activities and mechanisms that activate the p53 pathway, restoring response to therapy in haematological malignancies.

Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a∼125b cluster function by seed-targeting inhibitors in multiple myeloma cells

“…16 Monoallelic deletion of TP53 in MM, which often occurs without mutation to the other allele, is associated with an extremely poor prognosis. 17 This supports the idea that a decrease in TP53 levels is associated with tumor progression and numerous reports have shown that therapeutic induction of TP53 might be particularly suitable for the treatment of hematological malignancies, 18 including MM. 19,20 Recent research shows that alteration of miRNA expression during progression from monoclonal gammopathy of undetermined significance (MGUS) to newly diagnosed MM could be partially responsible for TP53 inactivation in MM patients.…”

MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity

“…28 The mechanism for such resistance to apoptosis has been linked to the overexpression of MDM2 and to inactivation of p53. 29 Thus, drugs targeting inhibition of proteasome-mediated degradation of p53 has emerged as a vital research area in the search for novel therapeutic approaches. Hideshima et al first showed that velcade acts directly to inhibit the growth of MM cell lines and patient samples, assessed by MTT assay and DNA synthesis.…”

RITA Inhibits Multiple Myeloma Cell Growth through Induction of p53-Mediated Caspase-Dependent Apoptosis and Synergistically Enhances Nutlin-Induced Cytotoxic Responses

“…MDM2 is the principal endogenous negative regulator of p53 and is an E3 ligase, which binds to the amino terminal p53 and facilitates proteasomal degradation of p53 (11,12). Due to the importance of the p53-MDM2 interaction, pharmacologic activation of the p53 pathway by inhibition of MDM2 binding has been shown to be an alternative therapeutic strategy in various cancers, including hematologic malignancies (13,14).…”