J Cancer 2021; 12(18):5519-5529. doi:10.7150/jca.52641 This issue

Research Paper

Suppression Of Aberrant Activation Of NF-κB Pathway In Drug-resistant Leukemia Stem Cells Contributes To Parthenolide-potentiated Reversal Of Drug Resistance In Leukemia

Juan Yi1*, Li Wang1*, Xiao-Yan Wang3, Jing Sun2, Xiao-Yang Yin1, Jin-Xia Hou1, Jing Chen1, Bei Xie1, Hu-Lai Wei1,4✉

1. School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
2. Lanzhou University Second Hospital, 80 Cui Ying Men, Lin Xia Road, Lanzhou, 730000 Gansu, China
3. Gansu Provincial Maternity and Childcare Hospital, 143 North Street, Qi Li He district, Lanzhou, 730050, Gansu, China
4. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China
*These authors contribute equally to this work

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Citation:
Yi J, Wang L, Wang XY, Sun J, Yin XY, Hou JX, Chen J, Xie B, Wei HL. Suppression Of Aberrant Activation Of NF-κB Pathway In Drug-resistant Leukemia Stem Cells Contributes To Parthenolide-potentiated Reversal Of Drug Resistance In Leukemia. J Cancer 2021; 12(18):5519-5529. doi:10.7150/jca.52641. Available from https://www.jcancer.org/v12p5519.htm

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Abstract

Graphic abstract

Although many drugs that targeted the specific features of leukemia stem cells (LSCs) have substantial application in the clinical treatment of leukemia, the LSCs relapsed and caused drug-resistant leukemia. Therefore, it is necessary to identify the unique features of LSCs in relapsing and drug-resistant leukemia and also to explore the drugs that directed at these features. Our clinical data have indicated that relapsed patients with acute myeloid leukemia have more abundant proportion of LSCs with enhanced breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) expression when compared to the untreated patients. The results showed that compared with LSCs derived from sensitive K562 cells, LSCs from drug-resistant K562/ADM cells have much higher chemotherapeutic resistance, and so we termed these cells as “drug-resistant LSCs”. Subsequently, aberrant activation of NF-κB pathway in drug-resistant LSCs was further using gene chip analysis. Also, parthenolide (PTL), which is a specific NF-κB inhibitor, effectively eliminated drug-resistant LSCs and enhanced the sensitivity of K562/ADM cells to doxorubicin-induced apoptosis by down-regulating NF-κB pathway-mediated P-gp expression. These findings make the research area of LSCs more abundant and provide a potential therapeutic strategy for the treatment of refractory and relapsed leukemia.

Keywords: Drug-resistant leukemia stem cells, PTL, NF-κB signaling pathway, MDR, aberrant activation