Effect of Triptolide on drug resistance in acute B-lymphoblastic leukemia by inhibiting PI3K/Akt-VCAM-1 pathway in bone marrow mesenchymal stem cells
YAO Yun-qian
JIA Xi
CHEN Xin-yuan
LI Qiu-xiao
SHI Peng-cheng
Abstract：Objective To investigate the role and molecular mechanism of low-concentration triptolide(TPL)in reversing bone marrow mesenchymal stem cell(MSC)-induced resistance to cytarabine(AraC)in acute B-lympho-blastic leukemia(B-ALL).Methods A co-culture model of B-ALL cell line Nalm6 and MSCs from ALL patients was established.The co-culture model was treated with TPL,AraC,or their combination.Nalm6 and MSCs were isola-ted,and cell proliferation was assessed using the CCK-8 assay.Cell apoptosis was measured using the Annexin V-PI kit.Western blot analysis was performed to detect PI3K/Akt signaling pathway protein expression in MSCs,and flow cy-tometry was used to measure VCAM-1 expression on the surface of MSCs.Results The IC50 of AraC in MSCs-co-cultured Nalm6 cells after 48 hours was significantly higher than in Nalm6 cells alone(P＜0.001),and the apoptosis rate of MSCs-co-cultured Nalm6 cells at 72 hours was significantly lower than in Nalm6 cells alone(P＜0.001).The IC50 of AraC in MSCs-co-cultured Nalm6 cells treated with IC20 concentration of TPL(2 nmol/L)for 48 hours was signifi-cantly lower than AraC monotherapy(P＜0.001).Co-treatment with low concentrations of TPL(2 nmol/L)and AraC(0.2 μmol/L)for 48 hours resulted in a significantly higher apoptosis rate in MSCs-co-cultured Nalm6 cells compared to TPL or AraC alone(P＜0.001).Western blot analysis showed that the combined treatment group exhibited significant downregulation of PI3Kp110δ,p-AKT,and p-GSK-3 β compared to the monotherapy and control groups.Moreover,the expression level of VCAM-1 in the combined treatment group was significantly lower than in the TPL,AraC,and control groups.Conclusion Low-concentration TPL may enhance the cytotoxicity of AraC against B-ALL by inhibiting the PI3K/Akt-VCAM-1 signaling pathway in MSCs.
Keywords：triptolidecytarabinemesenchymal stem cellsPI3 K/Aktacute B-lymphoblastic leukemiadrug resistance reversal
Publication Date：2025-04-15
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：6( 513-518 )