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

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 (∆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. 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.

(RS)-Tricarbon-yl(η-1,3-diacet-oxy-5,5-dimethyl-cyclo-hexa-1,3-diene)iron(0).

In the title compound, [Fe(C(12)H(16)O(4))(CO)(3)], the diene moiety of the mol-ecule is virtually planar, with a C-C-C-C torsion angle of -1.4 (2)°. The six-membered ring exhibits a boat conformation, with torsion angles of 46.2 (2) and 46.5 (3)° for a double-bond and the two attached Csp(3) atoms. The Fe atom is coordinated to all four of the diene C atoms, with bond lengths between 2.041 (2) and 2.117 (2) Å. The Fe(CO)(3) tripod adopts a conformation with one CO ligand eclipsing the Csp(3)-Csp(3) single bond.

Acyloxybutadiene tricarbonyl iron complexes as enzyme-triggered CO-releasing molecules (ET-CORMs): a structure-activity relationship study.

A series of η(4)-acyloxycyclohexadiene-Fe(CO)(3) complexes was prepared and fully characterized by spectroscopic methods including single crystal X-ray diffraction. For this purpose a new synthetic access to differently acylated 1,3- and 1,5-dienol-Fe(CO)(3) complexes was developed. The enzymatically triggered CO release from these compounds was monitored (detection of CO through GC and/or by means of a myoglobin assay) and the anti-inflammatory effect of the compounds was assessed by a cellular assay based on the inhibition of NO-production by inducible NO synthase (iNOS). It was demonstrated that the properties (rate of esterase-triggered CO release, iNOS inhibition, cytotoxicity) of the complexes strongly depend on the substitution pattern of the π-ligand and the nature of the acyloxy substituent.