title: Cordycepin disrupts leukemia association with mesenchymal stromal cells and eliminates leukemia stem cell activity.
abstract: Maintaining stemness of leukemic stem cells (LSCs) and reciprocal interactions between leukemia and stromal cells support leukemic progression and resistance to chemotherapy. Targeting the niche-based microenvironment is thus a new approach for leukemia therapy. Cordycepin is an analogue of adenosine and has been suggested to possess anti-leukemia properties. However, whether cordycepin influences association of leukemia and mesenchymal stromal cells has never been investigated. Here we show that cordycepin reduces CD34+CD38-cells in U937 and K562 cells and induces Dkk1 expression via autocrine and paracrine regulation in leukemia and mesenchymal stromal/stem cells (MSCs). Cordycepin suppresses cell attachment of leukemia with MSCs and downregulates N-cadherin in leukemia and VCAM-1 in MSCs. Moreover, incubation with leukemic conditioned media (CM) significantly induces IL-8 and IL-6 expression in MSCs, which is abrogated by cordycepin. Suppression of leukemic CM-induced VCAM-1 and IL-8 by cordycepin in MSCs is mediated by impairing NFκB signaling. Finally, cordycepin combined with an adenosine deaminase inhibitor prolongs survival in a leukemic mouse model. Our results indicate that cordycepin is a potential anti-leukemia therapeutic adjuvant via eliminating LSCs and disrupting leukemia-stromal association.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Shu-Man
authors.initials: SM
authors.lastname: Liang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Yi-Jhu
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.affiliation: Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Yee-Jee
authors.initials: YJ
authors.lastname: Jan
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D016019:Survival Analysis; D016896:Treatment Outcome; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D003839:Deoxyadenosines; C058120:cordycepin