RITA enhances chemosensivity of pre-B ALL cells to doxorubicin by inducing p53-dependent apoptosis.

Abstract

The use of low-molecular-weight, non-peptidic molecules that disrupt the interaction between the p53 tumor suppressor and its negative regulator MDM2 has provided a promising alternative for the treatment of different types of cancer. Here, we used small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) to sensitize leukemic NALM-6 cells to doxorubicin by upregulating p53 protein. RITA alone effectively inhibited NALM-6 cells viability in dose-dependent manner as measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay and induced apoptosis as evaluated by flow cytometry, whereas RITA in combination with doxorubicin enhanced NALM-6 cells to doxorubicin-sensitivity and promoted doxorubicin induced apoptosis. Levels of p53 protein and its proapoptotic target genes, quantified by western blot and real-time PCR respectively, showed that expression of p53 was significantly increased after RITA treatment. Using p53 inhibitors PFT-alpha and PFT-mu it was shown that p53-mediated apoptosis induced by RITA can be regulated by both p53-transcription-dependent and -independent pathways. Moreover, RITA-induced apoptosis was accompanied by the activation of caspase-3 and PARP cleavage. Therefore, exploiting synergistic effects between RITA and chemotherapeutics might be an effective clinical strategy for leukemia chemotherapy.

• Authors: Ahmad Kazemi, Majid Safa, Atefeh Shahbazi
• Journal: Hematology (Amsterdam, Netherlands) (Hematology) Vol. 16 Issue 4 Pg. 225-31 (Jul 2011) ISSN: 1607-8454 [Electronic] England
• PMID: 21756539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Neoplasm Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• ZNF331 protein, human
• Doxorubicin
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• DNA-Binding Proteins (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, pharmacology)
• Drug Synergism
• Humans
• Neoplasm Proteins (administration & dosage, pharmacology)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)
• Up-Regulation