title: Cyclometallated iridium complexes inducing paraptotic cell death like natural products: synthesis, structure and mechanistic aspects.
abstract: Six mononuclear Ir complexes (1-6) using polypyridyl-pyrazine based ligands (L1 and L2) and {[cp*IrCl(μ-Cl)]2and [(ppy)2Ir(μ-Cl)]2} precursors have been synthesised and characterised. Complexes 1-5 have shown potent anticancer activity against various human cancer cell lines (MCF-7, LNCap, Ishikawa, DU145, PC3 and SKOV3) while complex 6 is found to be inactive. Flow cytometry studies have established that cellular accumulation of the complexes lies in the order 2 > 1 > 5 > 4 > 3 > 6 which is in accordance with their observed cytotoxicity. No changes in the expression of the proteins like PARP, caspase 9 and beclin-1, Atg12 discard apoptosis and autophagy, respectively. Overexpression of CHOP, activation of MAPKs (P38, JNK, and ERK) and massive cytoplasmic vacuolisation collectively suggest a paraptotic mode of cell death induced by proteasomal dysfunction as well as endoplasmic reticulum and mitochondrial stress. An intimate relationship between p53, ROS production and extent of cell death has also been established using p53 wild, null and mutant type cancer cells.
authors.affiliation: School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar-751007, India. srikanta@iitbbs.ac.in.
authors.forename: Suman Kumar
authors.initials: SK
authors.lastname: Tripathy
authors.affiliation: Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. hkims@skku.edu.
authors.forename: Umasankar
authors.initials: U
authors.lastname: De
authors.affiliation: School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar-751007, India. srikanta@iitbbs.ac.in.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Dehury
authors.affiliation: School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar-751007, India. srikanta@iitbbs.ac.in.
authors.forename: Paltan
authors.initials: P
authors.lastname: Laha
authors.affiliation: National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram - 695 019, Kerala, India.
authors.forename: Manas Kumar
authors.initials: MK
authors.lastname: Panda
authors.affiliation: Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. hkims@skku.edu.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar-751007, India. srikanta@iitbbs.ac.in.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Patra
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects; D006801:Humans; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects
chemical_list: D001688:Biological Products; D056831:Coordination Complexes; C497249:DDIT3 protein, human; D011719:Pyrazines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; D007495:Iridium; D020928:Mitogen-Activated Protein Kinases