title: Bisindole-PBD regulates breast cancer cell proliferation via SIRT-p53 axis.
abstract: In a previous study we reported the role of potent bisindole-PBD conjugate as an inclusion in the arsenal of breast cancer therapeutics. In breast cancer cell proliferation, PI3K/AKT/mTOR pathway plays a crucial role by prosurvival mechanism that inhibits programmed cell death. Here, 2 breast cancer cells lines, MCF-7 and MDA-MB-231 were treated with Vorinostat (suberoylanilide hydroxamic acid / SAHA) and bisindole-PBD (5b). We have investigated the effect on PI3K/AKT/mTOR pathway and SIRT expression including epigenetic regulation. There was consistent decrease in the level of PI3K, AKT, mTOR proteins upon treatment of 5b in both MCF-7 and MDA-MB-231 cell lines compared to untreated controls. Treatment with caspase inhibitor (Q-VD-OPH) confirmed that the effect of 5b on PI3K signaling was ahead of apoptosis. Real time PCR and western blot analysis showed profound reduction in the mRNA and protein levels of SIRT1 and SIRT2. Molecular docking studies also supported the interaction of 5b with various amino acids of SIRT2 proteins. Treatment with 5b caused epigenetic changes that include increase of acetylated forms of p53, increase of histone acetylation at p21 promoter as well as decrease in methylation state of p21 gene. Compound 5b thus acts as SIRT inhibitor and cause p53 activation via inhibition of growth factor signaling and activation of p53 dependent apoptotic signaling. This present study focuses bisindole-PBD on epigenetic alteration putting 5b as a promising therapeutic tool in the realm of breast cancer research.
authors.affiliation: a Centre for Chemical Biology; CSIR-Indian Institute of Chemical Technology ; Tarnaka, Hyderabad , India.
authors.forename: Pranjal
authors.initials: P
authors.lastname: Sarma
authors.affiliation: a Centre for Chemical Biology; CSIR-Indian Institute of Chemical Technology ; Tarnaka, Hyderabad , India.|b Functional Genomics and Gene Silencing Group; CSIR-Center for Cellular and Molecular Biology ; Hyderabad , India.
authors.forename: Indira
authors.initials: I
authors.lastname: Bag
authors.affiliation: a Centre for Chemical Biology; CSIR-Indian Institute of Chemical Technology ; Tarnaka, Hyderabad , India.|c School of Chemical & Biotechnology; SASTRA University ; Tirumalaisamudram, Thanjavur , India.
authors.forename: M Janaki
authors.initials: MJ
authors.lastname: Ramaiah
authors.affiliation: d Medicinal Chemistry and Pharmacology; CSIR-Indian Institute of Chemical Technology ; Tarnaka, Hyderabad , India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: b Functional Genomics and Gene Silencing Group; CSIR-Center for Cellular and Molecular Biology ; Hyderabad , India.
authors.forename: Utpal
authors.initials: U
authors.lastname: Bhadra
authors.affiliation: a Centre for Chemical Biology; CSIR-Indian Institute of Chemical Technology ; Tarnaka, Hyderabad , India.
authors.forename: Manika
authors.initials: M
authors.lastname: Pal Bhadra
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Akt; SIRTs; docking; histone acetylation; p53 acetylation; p53 dependent genes; tubulin acetylation