Targeting hyaluronic acid production for the treatment of leukemia: Treatment with 4-methylumbelliferone leads to induction of MAPK-mediated apoptosis in K562 leukemia

• Published in: Leukemia research Vol. 37; no. 10; pp. 1294 - 1301
• Main Authors: Uchakina, Olga N, Ban, Hao, McKallip, Robert J
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2013
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Line, Tumor; CML; Disease Models, Animal; Extracellular Space - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Hyaluronic acid; Hyaluronic Acid - biosynthesis; Hymecromone - administration & dosage; Hymecromone - analogs & derivatives; Hymecromone - pharmacology; K562 Cells; Leukemia - metabolism; Leukemia - pathology; Mice; Mitogen-Activated Protein Kinases - metabolism; p38; p38 Mitogen-Activated Protein Kinases - metabolism; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; CML; p38; Hyaluronic acid; Apoptosis
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2013.07.009

Abstract The current study examined the effect of modulation of hyaluronic acid (HA) synthesis on leukemia cell survival using the hyaluronic acid synthesis inhibitor 4-methylumbelliferone (4-MU). Treatment of CML cells with 4-MU led to caspase-dependent apoptosis characterized by decreased HA production, PARP cleavage, and increased phosphorylation of p38. Addition of exogenous HA, the pan caspase inhibitor Z-VAD-FMK or the p38 inhibitor SB203580 to 4-MU treated cells was able to protect cells from apoptosis. Treatment of tumor-bearing mice with 4-MU led to a significant reduction in tumor load which was mediated through the induction of apoptosis.