PURPOSE: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. METHODS: CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. RESULTS: CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC(50) for CBDIV17 was ≈ 12 μM and ≈ 21 μM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC(50) of ≈ 46 μM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. CONCLUSIONS: Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.
PURPOSE: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. METHODS:CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. RESULTS:CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC(50) for CBDIV17 was ≈ 12 μM and ≈ 21 μM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC(50) of ≈ 46 μM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. CONCLUSIONS: Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.
Authors: C Sun; Y Shi; L L Xu; C Nageswararao; L D Davis; T Segawa; A Dobi; D G McLeod; S Srivastava Journal: Oncogene Date: 2006-04-24 Impact factor: 9.867
Authors: D Lecis; C Drago; L Manzoni; P Seneci; C Scolastico; E Mastrangelo; M Bolognesi; A Anichini; H Kashkar; H Walczak; D Delia Journal: Br J Cancer Date: 2010-05-11 Impact factor: 7.640
Authors: Berkley E Gryder; Michelle J Akbashev; Michael K Rood; Eric D Raftery; Warren M Meyers; Paulette Dillard; Shafiq Khan; Adegboyega K Oyelere Journal: ACS Chem Biol Date: 2013-09-20 Impact factor: 5.100
Authors: Di Wen; Deepak Chitkara; Hao Wu; Michael Danquah; Renukadevi Patil; Duane D Miller; Ram I Mahato Journal: Pharm Res Date: 2014-05-02 Impact factor: 4.200
Authors: Greg N Brooke; Simon C Gamble; Michael A Hough; Shajna Begum; D Alwyn Dart; Michael Odontiadis; Sue M Powell; Flavia M Fioretti; Rosie A Bryan; Jonathan Waxman; Robin Wait; Charlotte L Bevan Journal: Mol Cell Proteomics Date: 2015-02-18 Impact factor: 5.911
Authors: Andrea Lunardi; Ugo Ala; Mirjam T Epping; Leonardo Salmena; John G Clohessy; Kaitlyn A Webster; Guocan Wang; Roberta Mazzucchelli; Maristella Bianconi; Edward C Stack; Rosina Lis; Akash Patnaik; Lewis C Cantley; Glenn Bubley; Carlos Cordon-Cardo; William L Gerald; Rodolfo Montironi; Sabina Signoretti; Massimo Loda; Caterina Nardella; Pier Paolo Pandolfi Journal: Nat Genet Date: 2013-06-02 Impact factor: 38.330