Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
Sci Rep. 2017 Mar 7;7:43930. doi: 10.1038/srep43930.
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 CD34CD38 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.
维持白血病干细胞（LSCs）的干性和白血病与基质细胞之间的相互作用，支持白血病的进展和对化疗的耐药性。因此，靶向龛基微环境是白血病治疗的一种新方法。虫草素是一种腺苷类似物，已被证明具有抗白血病特性。然而，虫草素是否影响白血病与间充质基质细胞的关联从未被研究过。在这里，我们表明虫草素通过自分泌和旁分泌调节减少 U937 和 K562 细胞中的 CD34CD38 细胞，并诱导白血病和间充质基质/干细胞（MSCs）中的 Dkk1 表达。虫草素抑制白血病与 MSCs 的细胞黏附，并下调白血病中的 N-钙黏蛋白和 MSCs 中的 VCAM-1。此外，用白血病条件培养基（CM）孵育可显著诱导 MSCs 中 IL-8 和 IL-6 的表达，而虫草素可阻断这种表达。虫草素通过破坏 NFκB 信号通路，抑制白血病 CM 诱导的 MSCs 中 VCAM-1 和 IL-8 的表达。最后，虫草素联合腺苷脱氨酶抑制剂可延长白血病小鼠模型的生存期。我们的结果表明，虫草素通过消除 LSCs 和破坏白血病-基质关联，是一种有潜力的抗白血病治疗佐剂。
