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4-methylumbelliferone and imatinib combination enhances senescence induction in chronic myeloid leukemia cell lines

Investigational New Drugs volume 35, pages 1–10 (2017)Cite this article

Summary

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. Therefore, it is of great value to find molecules that enhance the anti-proliferative effect of first-line drugs. Hyaluronan is the main glycosaminglican of the extracellular matrix which is involved in tumor progression and multidrug resistance. We have previously demonstrated that the inhibition of hyaluronan synthesis by 4-methylumbelliferone (4MU) induces senescence and can revert Vincristine resistance in CML cell lines. However, the effect of 4MU on Imatinib therapy remains unknown. The aim of this work was to determine whether the combination of 4MU with Imatinib is able to modulate the proliferation as well as apoptosis and senescence induction in human CML cell lines. For this purpose the ATCC cell line K562, and its multidrug resistant derivate, Kv562 were used. Cells were exposed to 4MU, Imatinib or a combination of both. We demonstrated that 4MU and Imatinib co-treatment abrogated the proliferation of both cell lines. However, such co-treatment did not increase the levels of apoptosis when compared with the treatment with Imatinib alone. For both cell lines the mechanisms of tumor suppression involved was senescence, since the combination of 4MU and Imatinib arrested the cell cycle and increased senescence associated β-galactosidase activity and senescence associated heterochromatin foci presence when compared to each drug alone. Moreover, 4MU, Imatinib and 4MU + Imatinib decreased pAkt/Akt ratio in both cell lines and reduced the pERK/ERK ratio only in K562 cells. These findings highlight the potential use of 4MU together with Imatinib for CML therapy.

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Affiliations

  1. Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, 1113, Buenos Aires, Argentina

    Silvina Laura Lompardía, Mariángeles Díaz, Daniela Laura Papademetrio, Matías Pibuel, Élida Álvarez & Silvia Elvira Hajos

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  1. Silvina Laura Lompardía
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  2. Mariángeles Díaz
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  3. Daniela Laura Papademetrio
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  4. Matías Pibuel
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  5. Élida Álvarez
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Correspondence to Silvina Laura Lompardía.

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Author SLL declares that she has no conflict of interest. Author MD declares that she has no conflict of interest. Author DLP declares that she has no conflict of interest. Author MP declares that he has no conflict of interest. Author EA declares that she has no conflict of interest. Author SEH declares that she has no conflict of interest.

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This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (PIP N°0199 to SH); and Universidad de Buenos Aires (UBACYT B021 to SH), Argentina.

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Lompardía, S.L., Díaz, M., Papademetrio, D.L. et al. 4-methylumbelliferone and imatinib combination enhances senescence induction in chronic myeloid leukemia cell lines. Invest New Drugs 35, 1–10 (2017). https://doi.org/10.1007/s10637-016-0397-9

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  • DOI: https://doi.org/10.1007/s10637-016-0397-9

Keywords

  • Chronic myeloid leukemia
  • Imatinib
  • 4-methylumbelliferone
  • Senescence