Chronic myeloid leukemia is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome (Ph), generated by a reciprocal translocation occurring between chromosomes 9 and 22 [t(9;22)(q34;q11)]. As a consequence, a fusion gene (bcr-abl) encoding a constitutively active kinase is generated. The first-line treatment consists on BCR-ABL inhibitors such as Imatinib, Nilotinib and Dasatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, finding molecules that enhance the anti-proliferative effect of first-line drugs is of value. Hyaluronan oligomers (oHA) are known to be able to sensitize several tumor cells to chemotherapy. We have previously demonstrated that oHA can revert Vincristine resistance in mouse lymphoma and human leukemia cell lines. However, little is known about the role of oHA in hematological malignancies. The aim of this work was to determine whether oHA are able to modulate the anti-proliferative effect of Imatinib in chronic myeloid leukemia (CML) cell lines. The effect on apoptosis and senescence as well as the involvement of signaling pathways were also evaluated. For this purpose, the human CML cell lines K562 and Kv562 (resistant) were used. We demonstrated that oHA sensitized both cell lines to the anti-proliferative effect of Imatinib increasing apoptosis and senescence. Moreover, this effect would be accomplished through the down-regulation of the PI3K signaling pathway. These findings highlight the potential of oHA when used as a co-adjuvant therapy for chronic myeloid leukemia.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by poor prognosis and limited response to gemcitabine, the standard first-line chemotherapy. One major contributor to chemoresistance is autophagy, a process frequently upregulated in PDAC. In this study, we examined the ability of type I interferons (IFNα2b and IFNβ1a) to modulate autophagy and disturb tumor cell resistance to gemcitabine. PDAC cells were treated with increasing concentrations of IFNα2b or IFNβ1a, and cell proliferation was assessed by [³H]-thymidine incorporation. Apoptosis was evaluated by TUNEL staining following treatments with interferons and/or gemcitabine. Autophagy was analyzed by Western blot for LC3B and by quantifying autophagic flux using mCher-ry-EGFP-LC3B-transfected cells in the presence or absence of lysosomal inhibitors. We found that IFNα2b promoted autophagic flux and decreased gemcitabine-induced apop-tosis, indicating a cytoprotective role. In contrast, IFNβ1a inhibited autophagosome for-mation and significantly enhanced apoptosis in gemcitabine-treated cells. Our findings highlight the contrasting roles of IFNα2b and IFNβ1a in autophagy regulation and sug-gest that IFNβ1a, by inhibiting protective autophagy, may sensitize PDAC cells to chemo-therapy. This positions IFNβ1a as a promising adjuvant to overcome chemoresistance in PDAC treatment.