Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden

Molecular Cancer

Research

Carmen D. Herling¹  Michael Hallek¹  Dimitrios Mougiakakos²  Corazon Frias³  Aram Prokop³  Christoph Hirschhäuser⁴  Hans-Günther Schmalz⁴  Steffen Romanski⁴  Christian Prinz⁵  Marco Herling⁵  Gregor Lohmann⁵  Alexandra Schrader⁵  Petra Mayer⁵  Elena Vasyutina⁵ 

[1] Department I of Internal Medicine, CIO Köln-Bonn, and CECAD, University of Cologne, Cologne, Germany;Department of Internal Medicine, University of Erlangen, Erlangen, Germany;Department of Pediatric Hematology/Oncology, Children’s Hospital Cologne, Cologne, Germany;Division of Organic Chemistry, University of Cologne, Cologne, Germany;Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany;

关键词: CLL;    ROS;    Organometallic nucleosides;    TCL1;    Mitochondrial respiration;   

DOI  :  10.1186/s12943-015-0378-1

 received in 2014-09-05, accepted in 2015-05-05,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundRedox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable.MethodsBio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5’-CH2O-TDS substituent. Four of these metal-containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1-transgenic splenocytes.ResultsThe MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA-evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA-triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (∆ΨM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis.ConclusionsRedox-active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis.

【 授权许可】

Unknown   
© Prinz et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.