Producción CyT
Medicina - 4-METHYLUMBELLIFERONE INDUCES SENESCENCE AND SENSITIZES THE RESISTANT CML CELL LINE Ki562 TO THE EFFECT OF IMATINIB
Congreso
Autoría:
Ledesma MM ; Poodts D. ; Amoia, Sofía ; Vay ; AF Fundia ; Alvarez E. M. C. ; Hajos S. ; Pibuel M ; Lompardía S. L.Fecha:
2022Editorial y Lugar de Edición:
SAICResumen *
CML is myeloproliferative neoplasia, whose first-line therapy is BCR-ABL inhibitors such as Imatinib (IM). Although IM is effective, its prolonged use exerts a pressure capable of leading to the selection of resistant leukemic cells. Previously, we demonstrated that 4-methylumbelliferone (4MU) synergistic effect with IM on K562 and Kv562 cell growth inducing senescence. Subsequently, Ki562 cells were obtained by culturing K562 cells with increasing doses of IM from 0.1µM up to 1µM. To develop Ko562 control cells, K562 were kept in a culture presenting the same aging but without the selection pressure of IM. K562 and Ko562 are sensitive to IM effects, while Ki562 and Kv562 resist through overexpression of BCR-ABL and Pgp/PI3K activation, respectively. This work aimed to evaluate the effect of 4MU on Ko562 and Ki562 cells and to characterize the protein profile impact on all CML cell lines described above. Metabolic activity was evaluated by XTT, senescence induction by SA-β-gal (X-gal) and SAHF (DAPI), cell death by IP (FC), and protein profile by MALDI-TOF-MS. 4MU decreased the metabolic activity on Ko562 and Ki562 cell lines (p<0.01), increasing the percentage of cells SA-β-gal+ and with SAHF (p<0.05) without modifying the percentage of PI+ cells concerning untreated control. Moreover, the co-treatment with 4MU+IM inhibited metabolic activity more than each drug alone in both cell lines (p<0.01) without modifying the percentage of PI+ cells. MALDI-TOF-MS profiling by Hierarchical k-means clustering-Principal Component Analysis allowed us to differentiate the four CML cell lines by their chemotherapy-resistant phenotype (PC1+PC2 > 70% of variation). Furthermore, 4MU modulates these protein profiles, which were also differentiated by the former technique. We conclude that 4MU shows a cytostatic effect mediated by the induction of senescence and enhances the IM effect, supporting the hypothesis of 4MU as a potential drug for CML treatment even against IM-resistant leukemia cells. Información suministrada por el agente en SIGEVAPalabras Clave
SENESCENCEMALDI-TOF-MSCMLIMATINIB