title: Trans-dichlorooxovandium (IV) complex as a novel photoinducible DNA interstrand crosslinker for cancer therapy.
abstract: Although DNA interstrand crosslinking (ICL) agents such as mitomycin C, cisplatin and psoralen serve as potent anticancer drugs, these agents are known to have dose-limiting toxic effects on normal cells. Moreover, tumor resistance to these agents has been reported. Here, we show that trans-dichlorooxovanadium (IV) complex of pyrenyl terpyridine (VDC) is a novel photoinducible DNA crosslinking agent. By a combination of in vitro and ex vivo experiments including plasmid-based assays, we find that VDC forms monoadducts on the DNA and can be activated by UV-A and visible light to generate DNA interstrand crosslinks. VDC efficiently activates Fanconi anemia (FA) pathway of DNA interstrand crosslink repair. Strikingly, photoinduction of VDC induces prolonged activation of cell cycle checkpoint and a high degree of cell death in homologous recombination (HR)/ICL repair defective cells. Moreover, VDC specifically targets cells that express pathological RAD51C mutants. These data imply that VDC can be potentially used for cancer therapy and suggest that tumors arising in patients with gene mutations in FA and HR repair pathway can be specifically targeted by a photoactivatable VDC.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.|Present address: NNF Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, DK-2200, Copenhagen N.
authors.forename: Kumar
authors.initials: K
authors.lastname: Somyajit
authors.affiliation: Department of Inorganic and physical Chemistry, Indian Institute of Science, Bangalore 560012, India and.|Present address: Department of Chemistry, University of Gerogia, Athens, GA 30602, USA.
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Banik
authors.affiliation: Department of Biochemistry , Indian Institute of Science , Bangalore 560012 , India.
authors.forename: Sneha
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Department of Biochemistry , Indian Institute of Science , Bangalore 560012 , India.
authors.forename: Sharath
authors.initials: S
authors.lastname: Babu
authors.affiliation: Department of Physiology , NUS Yong Loo Lin School of Medicine , Singapore.
authors.forename: Manoor Prakash
authors.initials: MP
authors.lastname: Hande
authors.affiliation: Department of Inorganic and physical Chemistry , Indian Institute of Science , Bangalore 560012 , India and.
authors.forename: Akhil R
authors.initials: AR
authors.lastname: Chakravarty
authors.affiliation: Department of Biochemistry , Indian Institute of Science , Bangalore 560012 , India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Nagaraju
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D056831:Coordination Complexes / Q000493:pharmacokinetics*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018736:DNA Adducts / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D017319:Photosensitizing Agents / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D017319:Photosensitizing Agents; C000609223:dichlorooxo(pyrenyl terpyridine)vanadium(IV)