Alantolactone Induced Apoptosis And Cell Cycle Arrest Thro?gh Increasing Intracellular Reactive Oxygen Species Level In B Cell Acute Lymphoblastic Leukemia Cells

Altho?gh the prognosis of B cell acute lymphoblastic leukemia?B-ALL?has improved a lot with the application of standard combined chemotherapy,infant patients and adult patients with cytogenetic abnormalities,such as MLL gene rearrangement,BCR-ABL fusion oncogene,tend to have an unfavorable outcome.In the present study,we have found alantolactone?ALT?,an active component from natural product Inula helenium,has potent antitumor effect in B-ALL,especially in MLL-AF4 positive B-ALL with more obvious apoptosis in 24hrs treatment.Furthermore,alantolactone,showed good antitumor effecacy in primary cells from three B-ALL patients.A synthetic bioinformatics methods revealed that alantolactone,might exert its effect thro?gh reactive oxygen species?ROS?-induced DNA damage.In our study,we found that ALT induced accumulation of cellular ROS detected by ROS probe DHE and DCHF-DA and thus leaded to DNA damage determined by indicators 8-oxoG,p-ATM¹⁹⁸⁷,?-H2AX and comet assay.And excess DNA damage subsequently induced cell cycle arrest and cell apoptosis.In addition,we found alantolactone,significantly inhibited the activity of glutathione reductase?GR?,thioredoxin reductase?TrxR?and catalase,which account for its ROS-inducing effect.Finally,we tested its performance in B-ALL NOD-SCID mouse model,and found ALT predominantly prolonged the survival time,decreased the B-ALL cells infiltration and showed good tolerance.In conclusion,alantolactone,could be a potent candidate therapeutic in the treatment of B-ALL.