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Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):546-555
Acute Lymphoblastic Leukemia
Targeting the endoplasmic reticulum- mitochondria interface sensitizes leukemia cells to cytostatics
Fabian Koczian,1 Olga Nagło,1 Jan Vomacka,2 Binje Vick,3 Phil Servatius,4 Themistoklis Zisis,1 Britta Hettich,1 Uli Kazmaier,4 Stephan A. Sieber,2 Irmela Jeremias,3 Stefan Zahler1 and Simone Braig1
1Department of Pharmaceutical Biology, Ludwig Maximilian University of Munich;
2Department of Chemistry, Technical University of Munich, Garching; 3Research Unit
Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health,
4
Munich and Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany
ABSTRACT
Combination chemotherapy has proven to be a favorable strategy to treat acute leukemia. However, the introduction of novel com- pounds remains challenging and is hindered by a lack of under- standing of their mechanistic interactions with established drugs. In the present study, we demonstrate a highly increased response of various acute leukemia cell lines, drug-resistant cells and patient-derived xenograft cells by combining the recently introduced protein disulfide isomerase inhibitor PS89 with cytostatics. In leukemic cells, a pro- teomics-based target fishing approach revealed that PS89 affects a whole network of endoplasmic reticulum homeostasis proteins. We elucidate that the strong induction of apoptosis in combination with cytostatics is orchestrated by the PS89 target B-cell receptor-associated protein 31, which transduces apoptosis signals at the endoplasmic reticulum -mito- chondria interface. Activation of caspase-8 and cleavage of B-cell recep- tor-associated protein 31 stimulate a pro-apoptotic crosstalk including release of calcium from the endoplasmic reticulum and an increase in the levels of reactive oxygen species resulting in amplification of mitochon- drial apoptosis. The findings of this study promote PS89 as a novel chemosensitizing agent for the treatment of acute leukemia and uncov- ers that targeting the endoplasmic reticulum - mitochondrial network of cell death is a promising approach in combination therapy.
Introduction
Despite the significant success in the management of childhood acute lym- phoblastic leukemia (ALL) and acute myeloid leukemia (AML) with survival rates of >80% and >60%, respectively,1 the outcome of patients with relapsed or chemoresistant leukemia is still dismal.2,3 Especially in older patients, the balance of tolerable dosing versus effective cytotoxicity remains a major challenge. This issue is further exacerbated by the development of leukemic cell chemoresistance, which has been demonstrated for several cytostatics including tubulin binders and topoi- somerase inhibitors.4,5 In addition, the emergence of relapse-specific mutations of cancer cells is often associated with resistance to thiopurines and glucocorticoids.6,7 Thus, novel pharmaceutical options are urgently needed for the improvement of current treatment regimens.
There is general consenius that combination therapies benefit from the crosstalk of antileukemic agents, however the mechanisms of interaction have only been explored for a few.8 Therefore, drug discovery is not only encouraged to identify novel compounds and targets, but also to enhance the understanding of their inter- dependence with established cytostatics. The concept of network pharmacology has raised great interest in recent years, especially regarding complex disease sys- tems such as cancer.8,9 Following this principle, multi-target strategies, rather than the ‘one drug, one target’ paradigm, are proposed to be superior in rewiring cancer-
Correspondence:
SIMONE BRAIG
simone.braig@cup.uni-muenchen.de
Received: May 9, 2018. Accepted: October 4, 2018. Pre-published: October 11, 2018.
doi:10.3324/haematol.2018.197368
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/546
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