title: Enhanced anticancer activity of a combination of docetaxel and Aneustat (OMN54) in a patient-derived, advanced prostate cancer tissue xenograft model.
abstract: The current first-line treatment for advanced metastatic prostate cancer, i.e. docetaxel-based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti-prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase-I Clinical Trial. Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti-tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada. Electronic address: siqu@bccrc.ca.
authors.forename: Sifeng
authors.initials: S
authors.lastname: Qu
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada. Electronic address: kwang@prostatecentre.com.
authors.forename: Kendric
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada. Electronic address: hxue@bccrc.ca.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada. Electronic address: yuwang@bccrc.ca.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada. Electronic address: rwu@bccrc.ca.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, CA, USA. Electronic address: chengfei.liu@ucdmc.ucdavis.edu.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, CA, USA. Electronic address: acgao@ucdavis.edu.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada. Electronic address: pgout@bccrc.ca.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gout
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: ccollins@prostatecentre.com.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: ywang@bccrc.ca.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D000077143:Docetaxel; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D043823:Taxoids; D000077143:Docetaxel
keywords: Advanced prostate cancer; Aneustat; Docetaxel; Microarray; OMN54