title: Cytotoxicity and apoptosis induced by a plumbagin derivative in estrogen positive MCF-7 breast cancer cells.
abstract: Plumbagin [5-hydroxy- 2-methyl-1, 4-naphthaquinone] is a well-known plant derived anticancer lead compound. Several efforts have been made to synthesize its analogs and derivatives in order to increase its anticancer potential. In the present study, plumbagin and its five derivatives have been evaluated for their antiproliferative potential in one normal and four human cancer cell lines. Treatment with derivatives resulted in dose- and time-dependent inhibition of growth of various cancer cell lines. Prescreening of compounds led us to focus our further investigations on acetyl plumbagin, which showed remarkably low toxicity towards normal BJ cells and HepG2 cells. The mechanisms of apoptosis induction were determined by APOPercentage staining, caspase-3/7 activation, reactive oxygen species production and cell cycle analysis. The modulation of apoptotic genes (p53, Mdm2, NF-kB, Bad, Bax, Bcl-2 and Casp-7) was also measured using real time PCR. The positive staining using APOPercentage dye, increased caspase-3/7 activity, increased ROS production and enhanced mRNA expression of proapoptotic genes suggested that acetyl plumbagin exhibits anticancer effects on MCF-7 cells through its apoptosis-inducing property. A key highlighting point of the study is low toxicity of acetyl plumbagin towards normal BJ cells and negligible hepatotoxicity (data based on HepG2 cell line). Overall results showed that acetyl plumbagin with reduced toxicity might have the potential to be a new lead molecule for testing against estrogen positive breast cancer.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sagar
authors.forename: Luke
authors.initials: L
authors.lastname: Esau
authors.forename: Basem
authors.initials: B
authors.lastname: Moosa
authors.forename: Niveen M
authors.initials: NM
authors.lastname: Khashab
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Bajic
authors.affiliation: Computational Bioscience Research Center (CBRC), Building 2, Level 4, R-4336, King Abdullah University of Science and Technology (KAUST), Thuwal- 23955-6900, Kingdom of Saudi Arabia. mandeep.kaur@kaust.edu.sa.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Kaur
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D008297:Male; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D053148:Caspase 3; D053179:Caspase 7; C014758:plumbagin