Background Redox tension is a hallmark from the rewired metabolic phenotype of tumor. chemistry provided substances formulated with a cytosine nucleobase a steel primary (ferrocene ruthenocene Fe(CO)3) and a 5’-CH2O-TDS substituent. Four of the metal-containing nucleoside analogues (MCNA) had been tested because of their efficacy and setting of actions in CLL individual examples gene-targeted cell lines and murine TCL1-transgenic splenocytes. Outcomes a marked was showed with the MCNA and selective cytotoxicity towards CLL cells. MCNA activity was similarly seen in high-risk disease groupings including those of del11q/del17p cytogenetics and of scientific fludarabine level of resistance. They overcame LG 100268 defensive PAP-A stromal cell connections. MCNA-evoked PARP-mediated cell loss of life was non-autophagic and non-necrotic aswell as caspase- and P53-indie. This unconventional apoptosis included early boosts of ROS which demonstrated indispensible predicated on mitigation of MCNA-triggered loss of life by different scavengers. MCNA publicity decreased mitochondrial respiration (air consumption price; OCR) and induced an instant membrane depolarization (?ΨM). These features 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 LG 100268 triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial dynamic flux and renders them more susceptible towards brokers interfering in mitochondrial homeostasis. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0378-1) contains supplementary material which is available to authorized users. Keywords: CLL ROS Organometallic nucleosides TCL1 Mitochondrial respiration Introduction The current therapeutic challenges in cancer including chronic lymphocytic leukemia (CLL) the most prevalent leukemia LG 100268 of adults in the western world involve the targeting of tumor-specific pathways in a more profound fashion than accomplished by conventional cytostatics [1]. In CLL chemo-immunotherapies with nucleosides like fludarabine in combination with antibodies have significantly improved response rates [2] but the majority of patients LG 100268 eventually relapse due to incomplete clonal eradication and finally develop refractory disease. A major underlying reason for such treatment failures are resistances of the leukemic (sub)clones towards drug-induced 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. The latter is particularly found in the clinically high-risk subsets of 11q23/ATM or 17p/TP53 deleted/mutated CLL [5 6 A key to overcome such high thresholds for classical apoptosis would be to exploit impartial forms of (programmed) cell death. Such therapeutic strategies would bypass major modes of resistance to most currently used substances. We previously identified organochalcogens (organoselenium -tellurium compounds) to act as ‘sensor/effector’ catalysts of reactive oxygen species (ROS) particularly in a specific tumor-to-normal cell fashion across various malignancy 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. The therapeutic potential.