title: Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer.
abstract: Many botanical compounds have been proposed to prevent cancer. We investigated the cancer treatment and prevention abilities of apigenin, baicalein, curcumin, epigallocatechin 3-gallate (EGCG), genistein, quercetin, and resveratrol both in vivo in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice as well as in vitro in prostate cancer cell lines. In our experiments, these seven compounds act similarly to the Hedgehog antagonist cyclopamine, a teratogenic plant alkaloid, which had been previously shown to "cure" prostate cancer in a mouse xenograft model. With IC(50) values ranging from <1 to 25 mumol/L, these compounds can inhibit Gli1 mRNA concentration by up to 95% and downregulate Gli reporter activity by 80%. We show that four compounds, genistein, curcumin, EGCG, and resveratrol, inhibit Hedgehog signaling as monitored by real-time reverse transcription-PCR analysis of Gli1 mRNA concentration or by Gli reporter activity. Three compounds, apigenin, baicalein, and quercetin, decreased Gli1 mRNA concentration but not Gli reporter activity. Our results show that these compounds are also able to reduce or delay prostate cancer in vivo in TRAMP mice. All seven compounds, when fed in combination as pure compounds or as crude plant extracts, inhibit well-differentiated carcinoma of the prostate by 58% and 81%, respectively. In vitro, we show that all seven compounds also inhibit growth in human and mouse prostate cancer cell lines. Mechanistically, we propose the Hedgehog signaling pathway to be a direct or indirect target of these compounds. These botanicals at pharmacologic concentrations are potentially safer and less expensive alternatives to cyclopamine and its pharmaceutical analogues for cancer therapy.
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Slusarz
authors.forename: Nader S
authors.initials: NS
authors.lastname: Shenouda
authors.forename: Mary S
authors.initials: MS
authors.lastname: Sakla
authors.forename: Sara K
authors.initials: SK
authors.lastname: Drenkhahn
authors.forename: Acharan S
authors.initials: AS
authors.lastname: Narula
authors.forename: Ruth S
authors.initials: RS
authors.lastname: MacDonald
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Besch-Williford
authors.forename: Dennis B
authors.initials: DB
authors.lastname: Lubahn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy / Q000379:methods; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; C506034:Tnfrsf25 protein, mouse