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Acute Lymphoblastic Leukemia
Investigating chemoresistance to improve sensitivity of childhood T-cell acute lymphoblastic leukemia to parthenolide
Ferrata Storti Foundation
Benjamin C. Ede,1 Rafal R Asmaro,1 John P. Moppett,1,2 Paraskevi Diamanti1,3 and Allison Blair1,3
1School of Cellular and Molecular Medicine, University of Bristol; 2Bristol Royal Hospital for Children and 3Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, UK
Haematologica 2018 Volume 103(9):1493-1501
ABSTRACT
Current therapies for childhood T-cell acute lymphoblastic leukemia have increased survival rates to above 85% in devel- oped countries. Unfortunately, some patients fail to respond to therapy and many suffer from serious side effects, highlighting the need to investigate other agents to treat this disease. Parthenolide, a nuclear factor kappa (κ)B inhibitor and reactive oxygen species inducer, has been shown to have excellent anti-cancer activity in pediatric leukemia xenografts, with minimal effects on normal hemopoietic cells. However, some leukemia initiating cell populations remain resistant to partheno- lide. This study examined mechanisms for this resistance, including pro- tective effects conferred by bone marrow stromal components. T-cell acute leukemia cells co-cultured with mesenchymal stem cells demon- strated significantly enhanced survival against parthenolide (73±11%) compared to cells treated without mesenchymal stem cell support (11±9%). Direct cell contact between mesenchymal cells and leukemia cells was not required to afford protection from parthenolide. Mesenchymal stem cells released thiols and protected leukemia cells from reactive oxygen species stress, which is associated with partheno- lide cytotoxicity. Blocking cystine uptake by mesenchymal stem cells, using a small molecule inhibitor, prevented thiol release and significantly reduced leukemia cell resistance to parthenolide. These data indicate it may be possible to achieve greater toxicity to childhood T-cell acute lymphoblastic leukemia by combining parthenolide with inhibitors of cystine uptake.
Introduction
The introduction of contemporary therapies for childhood T-cell acute lym- phoblastic leukemia (T-ALL) has resulted in remission rates that are closer to that of B-cell precursor (BCP) ALL but survival rates remain lower and 15-20% of chil- dren with T-ALL die from relapsed/refractory disease.1 Patients with high-risk dis- ease or those who relapse often receive more intensive treatment, making them more susceptible to toxicity and long-term secondary complications.2 This high- lights the need to investigate other agents to treat this disease.
It has been demonstrated that numerous cancers generate high levels of reactive oxygen species (ROS) compared to healthy tissue counterparts, where ROS levels are normally maintained in a tightly controlled manner.3 In T-ALL, ROS levels have been shown to be heightened, and this can inactivate phosphatase and the tensin homolog (PTEN), promoting leukemia cell survival.4 In human T-ALL, ROS levels are restrained by downregulation of protein kinase c theta (PKCθ) caused by NOTCH-1, a commonly activated mutation in T-ALL.5 However, if ROS stress lev- els are pushed above a certain threshold, cell death is forced to occur.3 Therefore, ROS promoting drugs may be an effective way of targeting cancer cells. Parthenolide (PTL) has been previously shown by ourselves and others to be a promising therapeutic agent for blood cancers.6-8 Importantly, it has limited effects
Correspondence:
allison.blair@bristol.ac.uk
Received: December 18, 2017. Accepted: May 10, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2017.186700
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/9/1493
©2018 Ferrata Storti Foundation
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