Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0378-1) contains supplementary material, which is available to authorized users.
Highlights
The current therapeutic challenges in cancer, including chronic lymphocytic leukemia (CLL) the most prevalent leukemia of adults in the western world, involve the targeting of tumor-specific pathways in a more profound fashion than accomplished by conventional cytostatics [1]
The high T-cell leukemia 1 (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
Chemistry and selection of the novel organometallic nucleoside analogues We have been extensively studying butadiene Fe(CO)3complexes like Me-N69 and could show that their ironfragment is crucial for the cell death inducing activity in BJAB lymphoma cells [21]
Summary
The current therapeutic challenges in cancer, including chronic lymphocytic leukemia (CLL) the most prevalent leukemia of adults in the western world, involve the targeting of tumor-specific pathways in a more profound fashion than accomplished by conventional cytostatics [1]. A major underlying reason for such treatment failures are resistances of the leukemic (sub)clones towards druginduced triggering of classical apoptosis [3] Mediators of such protection in CLL are a marked pro-survival impact by micro-environmental niches [4] and genetic deficiencies to evoke an adequate p53 mediated apoptotic response. We previously identified organochalcogens (organoselenium, -tellurium compounds) to act as ‘sensor/ effector’ catalysts of reactive oxygen species (ROS), in a specific tumor-to-normal cell fashion across various cancer cell types, including CLL [7, 8] These substances exploited the aberrant redox equilibrium of enhanced radical production and reduced glutathione (GSH) buffer levels in CLL cells as their selective vulnerability by increasing the elevated ROS levels towards a cytotoxic threshold. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable
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