5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one and Leukemia--Myeloid--Acute

Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.

Topics: Antineoplastic Agents; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-myc; Purines; Quinazolinones; Thiazoles; Tumor Suppressor Protein p53

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.

Topics: Antineoplastic Agents; CCAAT-Enhancer-Binding Protein-beta; Cell Differentiation; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression; Humans; K562 Cells; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-myc; Thiazoles; Tretinoin