Universität zu Köln

Prinz, Christian, Vasyutina, Elena ORCID: 0000-0001-9722-3419, Lohmann, Gregor, Schrader, Alexandra, Romanski, Steffen, Hirschhaeuser, Christoph, Mayer, Petra, Frias, Corazon, Herling, Carmen D., Hallek, Michael, Schmalz, Hans-Guenther ORCID: 0000-0003-0489-1827, Prokop, Aram, Mougiakakos, Dimitrios and Herling, Marco (2015). Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden. Mol. Cancer, 14. LONDON: BMC. ISSN 1476-4598

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Abstract

Background: Redox 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. Methods: Bio-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. Results: The 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 (Delta psi M). 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. Conclusions: Redox-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Prinz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Vasyutina, Elena UNSPECIFIED orcid.org/0000-0001-9722-3419 UNSPECIFIED Lohmann, Gregor UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrader, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Romanski, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirschhaeuser, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Frias, Corazon UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Carmen D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmalz, Hans-Guenther UNSPECIFIED orcid.org/0000-0003-0489-1827 UNSPECIFIED Prokop, Aram UNSPECIFIED UNSPECIFIED UNSPECIFIED Mougiakakos, Dimitrios UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-401270
DOI:	10.1186/s12943-015-0378-1
Journal or Publication Title:	Mol. Cancer
Volume:	14
Date:	2015
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1476-4598
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Organic Chemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; OXIDATIVE STRESS; TCL1 EXPRESSION; APOPTOSIS; ANALOGS; ACTIVATION; CLL; FLUDARABINE; MECHANISMS; RESISTANCE Multiple languages Biochemistry & Molecular Biology; Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/40127