Human umbilical cord mesenchymal stem cells restore imatinib and doxorubicin sensitivity in drug-resistant chronic myeloid leukemia cells

Mesenchymal stem cells (MSCs) have therapeutic effects in different types of cancers. The physical contact of chronic myeloid leukemia (CML) cells with MSCs potentially induces apoptosis by activating Bax and downregulating Bcl-2. Herein, we elucidated whether human umbilical cord MSCs (hUC-MSCs) can modulate chemosensitivity in a CML cell line (K562) and a K562-derived imatinib-resistant cell line. Imatinib-resistant K562 cells were generated from sequential imatinib treatment of K562 cells. hUC-MSCs were isolated from the Wharton's jelly of an umbilical cord. After co-culture with hUC-MSCs, imatinib-sensitive and imatinib-resistant K562 cells were exposed to either imatinib or doxorubicin. Inhibition of tumor cell growth was based on cell viability, which was determined using annexin V/propidium iodide flow cytometry and MTS assays. Protein expression of Bax, Caspase3, CD44, FoxO3a, and MDR1 was measured using Western blotting. We found the presence of hUC-MSCs resulted in the loss of CD44 and inactivation of the FoxO3a-MDR1 (multidrug resistant gene ABCB1) signaling pathway that is dominant in imatinib-resistant K562 cell monoculture. Importantly, co-culture of hUC-MSCs with CML cells restored imatinib and doxorubicin sensitivity of the latter in vitro, as evidenced by a decrease in viability and an increase in apoptotic subpopulations. Our findings indicated that hUC-MSCs restore sensitivity to imatinib and doxorubicin in drug-resistant K562 cells by downregulating FoxO3a-MDR1 expression, and may thus serve as a therapeutic tool to overcome drug resistance in CML.