1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53

• Published in: Molecular cancer therapeutics Vol. 9; no. 5; pp. 1158 - 1168
• Main Authors: Thompson, Thelma, Andreeff, Michael, Studzinski, George P, Vassilev, Lyubomir T
• Format: Journal Article
• Language: English
• Published: United States 01.05.2010
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Calcitriol - administration & dosage; Calcitriol - pharmacology; Cell Differentiation - drug effects; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Synergism; Gene Expression Regulation, Leukemic - drug effects; Genes, p53; HL-60 Cells; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Monocytes - drug effects; Monocytes - physiology; Piperazines - administration & dosage; Piperazines - pharmacology; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Up-Regulation - drug effects
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-09-1036

The tumor suppressor p53 is often referred to as "the guardian of the genome" because of its central role in the cellular response to oncogenic stress and prevention of tumor development. Mutations of p53 in acute myeloid leukemia (AML) are rare but resistance to chemotherapy has been reported because of the deregulation of the p53 signaling and differentiation pathways. It is known that the interaction of the vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25D) with its functional vitamin D receptor leads to differentiation, G(1) arrest, and increased cell survival in p53-null AML cells. However, there are no reports on the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we examine vitamin D signaling in AML cells MOLM-13 and OCI-AML3 expressing wild-type p53 in the presence and absence of the MDM2 antagonist nutlin-3. We find that 1,25D alone induces monocytic differentiation in these cell lines similar to that seen in p53-null AML cells, suggesting that the presence of wild-type p53 is compatible with activation of vitamin D signaling. Combination of nutlin-3a with 1,25D accelerated programmed cell death, likely because of enhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and downregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, and phosphorylated extracellular signal-regulated kinase 2.