Abstract
Thiosemicarbazones (TSC) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation. Ribonucleotide reductase (RNR) is considered one of the main targets of TSCs, yet, the existence of additional targets, differently responsible for the multifaceted activities of TSCs and their metal complexes has been proposed. To set the basis for a more comprehensive delineation of their mode of action, we chemogenomically profiled the cellular effects of bis(citronellalthiosemicarbazonato)nickel(II) [Ni(S-tcitr)2] using the unicellular eukaryote Saccharomyces cerevisiae as a model organism. Two complementary genomic phenotyping screens led to the identification of 269 sensitive and 56 tolerant deletion mutant strains and of 14 genes that when overexpressed make yeast cells resistant to an otherwise lethal concentration of Ni(S-tcitr)2. Chromatin remodeling, cytoskeleton organization, mitochondrial function and iron metabolism were identified as lead cellular processes responsible for Ni(S-tcitr)2 toxicity. The latter process, and particularly glutaredoxin-mediated iron loading of RNR, was found to be affected by Ni(S-tcitr)2. Given the multiple pathways regulated by glutaredoxins, targeting of these proteins by Ni(S-tcitr)2 can negatively affect various core cellular processes that may critically contribute to Ni(S-tcitr)2 cytotoxicity.
Highlights
Thiosemicarbazones (TSC) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation
The antiproliferative activity of TSCs has been initially ascribed to their metal (e.g., F e2+) sequestration capacity and to the inactivation of ribonucleotide reductase (RNR), the enzyme that converts ribonucleotides into deoxyribonucleotides and whose activity correlates with cell proliferation[5,6]
The data presented in this work support a fairly peculiar mechanism for Ni(S-tcitr)[2] cytotoxicity, centered on the inhibition of monothiol Grx activity, which appears to be distinct from the mode of action of metal-free TSCs and other related compounds[4]
Summary
Thiosemicarbazones (TSC) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation. Further investigation has led to the development of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine)[13], whose efficacy is currently undergoing phase II clinical testing[14,15,16,17] This compound shows promising activity against hematologic disorders but not solid tumours[4]. The above effects appear to be distinct from those elicited by metal-free TSC ligands and independent from the p53 (wild-type or mutated) state, but highly selective for cycling cells such as phytoemagglutinin-stimulated lymphocytes and the human histiocytic lymphoma cell line U 93732,33 Despite this fairly extensive characterization, a unifying mode of action explaining the basic cellular and molecular mechanisms underlying Ni(S-tcitr)[2] cytotoxicity is presently not available –a lack of information that precludes a more causal understanding of the primary targets of Ni(S-tcitr)[2] and a reliable and accessible cellular readout for its further chemical improvement
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