Hyaluronan reverses Imatinib dependent-senescence in chronic myeloid leukemia cell lines.

PIBUEL M.; LEVERMANN M.; DÍAZ M.; MIHALEZ C.Y.; HAJOS S. E.; LOMPARDÍA S. L.; PAPADEMETRIO D. L.; ALVAREZ E. M. C.

Londres

Congreso; Glycobiology 2017; 2017

Glycobiology

Chronic myeloid leukemia (CML) is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome which encodes a constitutively activated tyrosine kinase (BCR-ABL). The first line treatment for CML consists on BCR-ABL inhibitors such as Imatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Hyaluronan (HA) is the main glycosaminoglycan of the extracellular matrix which is involved in tumor progression and multidrug resistance. We have previously demonstrated that HA induce cell proliferation in CML cells. However, the effect of HA on Imatinib therapy remains unknown. The aim of this work was to determine whether HA is able to reverse the anti-proliferative, pro-apoptotic and pro-senescent effect of Imatinib in human CML cell lines. For this purpose, K562 (ATCC) and Kv562 (multidrug resistant derived) were exposed to HA, Imatinib or a combination of both. Cell proliferation was evaluated by 3H-T uptake; apoptosis was determinated by annexin-V-PE-7AAD kit, SubG1 peak and DNA fragmentation; senescence was evaluated by senescence-associated β-galactosidase activity (SA-β-gal) and senescence-associated heterochromatin foci (SAHF) presence. We showed that HA reversed the anti-proliferative effect of Imatinib without modify Imatinib-dependent apoptosis in both cell lines. However, the combination of HA and Imatinib decreased SA-β-gal activity and SAHF presence when compared to Imatinib alone. Moreover, Imatinib treatment decreased pAkt/Akt ratio in both cell lines and reduced the pERK/ERK ratio only in K562 cells, while the addition of HA reversed such effects. We conclude that HA reverses de anti-proliferative and pro-senescent effect of Imatinib without modify apoptosis.