Inhibition of c-Myc Overcomes Cytotoxic Drug Resistance in Acute Myeloid Leukemia Cells by Promoting Differentiation

• Published in: PloS one Vol. 9; no. 8; p. e105381
• Main Authors: Pan, Xiao-Na, Chen, Jia-Jie, Wang, Le-Xun, Xiao, Ruo-Zhi, Liu, Ling-Ling, Fang, Zhi-Gang, Liu, Quentin, Long, Zi-Jie, Lin, Dong-Jun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.08.2014; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Antineoplastic Agents - pharmacology; Biology and Life Sciences; c-Myc protein; Cancer therapies; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell cycle; Cell Differentiation; Cell Proliferation; Chemotherapy; Colonies; Cytotoxicity; Differentiation (biology); Drug resistance; Drug Resistance, Neoplasm; Drugs; Gene Expression; Hematology; Humans; Inhibition; K562 Cells; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Medical screening; Medicine and Health Sciences; Melanoma; Myc protein; Myeloid leukemia; Overexpression; Polymerase chain reaction; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Retinoic acid; Thiazoles - pharmacology; Transcription factors; Tretinoin; Tretinoin - pharmacology; Western blotting; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0105381

Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML) treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA). Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.