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

Abstract

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.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…This already confers antiproliferative, proapoptotic, and antimetastatic effects in cultured tumor cells and implanted tumors (Yates et al, 2015;Nagase et al, 2017). The antitumor effect results from reduced CD44 activation that lowers PI3K signaling and AKT and ERK phosphorylation (Kundu et al, 2013;Lompardia et al, 2017). Others have shown that 4-MU increases p38 activation and caspase-3, caspase-9, and PARP cleavage, explaining not only the apoptotic effect but might also indicate an increased sensitivity toward cytotoxic stress (Lokeshwar et al, 2010;Uchakina et al, 2016).…”

Various Mechanisms Involve the Nuclear Factor (Erythroid-Derived 2)-Like (NRF2) to Achieve Cytoprotection in Long-Term Cisplatin-Treated Urothelial Carcinoma Cell Lines

“…In other cancer types, KEAP1 mutations in the first Kelch domain (e.g., G333C in A549 cells) and in the intervention region (IVR, D236H in H460 cells) modified NRF2 signalling and influenced platinum sensitivity [ 50 ]. Of note, in addition to p62/SQSTM1, other negative regulators of the NRF2–KEAP interaction, such as Gankyrin (PSMD10, 26S proteasome non-ATPase regulatory subunit 10) [ 61 , 62 ] could be involved and may deserve further investigation. In theory, KEAP1-mediated control of NRF2 might also be disrupted by the cyclin inhibitor p21 Cip1/Waf1 , which competes with oxidised KEAP1 for binding to the NRF2 DLG motif to enhance the stability of the transcription factor [ 21 , 63 , 64 , 65 , 66 ].…”

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

“…Furthermore, in vivo studies using prostate and pancreatic cancer murine tumor models, treatment with 4-MU also reduced HA accumulation [ 112 ]. Reduced CD44 activation led to decreased PI3K signaling and AKT and ERK phosphorylation [ 113 ]. In vivo studies using a murine pancreatic ductal adenocarcinoma (PDAC) model showed that the treatment with PEGylated human recombinant PH20 hyaluronidase (PEGPH20) reduces HA content and improves gemcitabine and DOX [ 114 ].…”