Methylumbelliferone and Imatinib combination enhances senescence induction in chronic myeloid leukemia cell lines

LOMPARDIA S L.,; DIAZ M; PAPADEMETRIO D,; PIBUEL M; ALVAREZ E; HAJOS, SE

INVESTIGATIONAL NEW DRUGS

SPRINGER

Lugar: Berlin; Año: 2017 vol. 31 p. 1 - 10

0167-6997

Summary Chronic myeloid leukemia (CML) is a myeloproliferativesyndrome characterized by the presence of thePhiladelphia chromosome which encodes a constitutively activatedtyrosine kinase (BCR-ABL). The first line treatment forCML consists on BCR-ABL inhibitors such as Imatinib.Nevertheless, such treatment may lead to the selection of resistantcells. Therefore, it is of great value to find moleculesthat enhance the anti-proliferative effect of first-line drugs.Hyaluronan is the main glycosaminglican of the extracellularmatrix which is involved in tumor progression and multidrugresistance. We have previously demonstrated that the inhibitionof hyaluronan synthesis by 4-methylumbelliferone(4MU) induces senescence and can revert Vincristine resistancein CML cell lines. However, the effect of 4MU onImatinib therapy remains unknown. The aim of this workwas to determine whether the combination of 4MU withImatinib is able to modulate the proliferation as well as apoptosisand senescence induction in human CML cell lines. Forthis purpose the ATCC cell line K562, and its multidrug resistantderivate, Kv562 were used. Cells were exposed to4MU, Imatinib or a combination of both. We demonstratedthat 4MU and Imatinib co-treatment abrogated the proliferationof both cell lines. However, such co-treatment did notincrease the levels of apoptosis when compared with the treatmentwith Imatinib alone. For both cell lines the mechanismsof tumor suppression involved was senescence, since the combinationof 4MU and Imatinib arrested the cell cycle and increasedsenescence associated β-galactosidase activity andsenescence associated heterochromatin foci presence whencompared to each drug alone. Moreover, 4MU, Imatinib and4MU + Imatinib decreased pAkt/Akt ratio in both cell linesand reduced the pERK/ERK ratio only in K562 cells. Thesefindings highlight the potential use of 4MU together withImatinib for CML therapy.Keywords Chronic myeloid leukemia . Imatinib .4-methylumbelliferone . Senescence