Triphenyltin(IV) dithiocarbamate compound induces genotoxicity and cytotoxicity in K562 human erythroleukemia cells primarily via mitochondria-mediated apoptosis. (October 2022)

• Record Type: Journal Article
• Authors: Syed Annuar, Sharifah Nadhira; Kamaludin, Nurul Farahana; Awang, Normah; Chan, Kok Meng
• Is Part Of: Food and chemical toxicology. Volume 168(2022)
• Publication Date: 2022-10
• Subjects: Organotin -- Apoptosis -- Cell cycle -- Caspase cascade -- Molecular; ADMET absorption, distribution, metabolism, excretion, and toxicity -- CML chronic myeloid leukemia -- DHE dihydroethidium -- DMSO dimethyl sulfoxide -- GSH glutathione -- MTT -(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazholium bromide -- NAC N-acetyl-L-cysteine -- OD optical density -- ROS reactive oxygen species -- SI selectivity index -- TBT tributyltin -- TMRE tetramethylrhodamine ethyl ester -- TPT triphenyltin; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2022.113336
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: The novel di-and triphenyltin(IV) dithiocarbamate compounds represented as Rn SnL2 (where R = C4 H9, C6 H5 ; n = 2, 3; L = N, N -dithiocarbamate), Ph2 Sn( N, N -diisopropyldithiocarbamate) (OC1 ), Ph3 Sn( N, N -diisopropyldithiocarbamate) (OC2 ), Ph2 Sn( N, N -diallyldithiocarbamate) (OC3 ), Ph3 Sn( N, N -diallyldithiocarbamate) (OC4 ), and Ph2 Sn( N, N -diethyldithiocarbamate) (OC5 ) were assessed for their cytotoxicity in K562 human erythroleukemia cells. All compounds inhibited the growth of cells at low micromolar concentrations (<10 μM), and the mechanism underlying their antiproliferative effects on K562 cells was apoptosis, as corroborated by the exposure of plasma membrane phosphatidylserine. OC2, which showed the most promising antiproliferative activity, was selected for further analyses. The results demonstrated that OC2 induced apoptosis in K562 cells via an intrinsic mitochondrial pathway triggered upon DNA damage, an early apoptotic signal. Subsequently, OC2 produced excessive intracellular reactive oxygen species. The role of oxidative stress was corroborated by the significant reduction in GSH levels and percentage of apoptosis in NAC-pretreated cells. OC2 could arrest the cell cycle progression in the S phase. These new findings elucidate the antiproliferative potential of OC2 in the K562 human erythroleukemia cells and warrant further investigation, specifically to determine the exact signaling pathway underlying its antileukemic efficacy. Graphical abstract: Image 1 Highlights: Triphenyltin(IV) diisopropyldithiocarbamate (OC2) is cytotoxic to K562 cells. OC2 induces apoptosis by DNA damage followed by MMP loss. Accumulation of ROS eventually activates the caspase cascade as well as cleaved-PARP. OC2 reduced GSH and apoptotic NAC-pretreated cells percentage proved oxidative stress as secondary effect. OC2 arrested cells in the S phase indicting its DNA-targeted action.