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

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.

Melittin induces human gastric cancer cell apoptosisviaactivation of mitochondrial pathway

“…ROS are important oxygen-containing substances in apoptosis that are produced during the process of cellular respiration [45] . The mitochondria play a key role in cell apoptosis and ROS production.…”

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

“…Another important result of the provided meta-analyses is the first description of elevated TCL1A in JAK and STAT mutated T-PLL. TCL1A overexpression is known to be associated with elevated levels of reactive oxygen species (ROS) [33]. In addition, an 8-oxoguanine DNA damage signature is characteristic for T-PLL, likely resulting from ROS-mediated DNA insults [9].…”

Metabolism pathways in chronic lymphocytic leukemia

“…Elevated ROS levels likely contribute to the lymph node’s protective milieu [49,50]. Therefore strategies to exploit the aberrant redox characteristics of CLL cells in order to induce apoptosis have been proposed [51]. Similarly, stromal cells provide cysteine for the synthesis of the antioxidant glutathione and, as a result, relieving ROS-derived oxidative stress [52].…”