title: Labda-8(17),12,14-trien-19-oic acid contained in fruits of Cupressus sempervirens suppresses benign prostatic hyperplasia in rat and in vitro human models through inhibition of androgen and STAT-3 signaling.
abstract: Fruit extract of Cupressus sempervirens (CS), which is used traditionally to treat Benign Prostatic Hyperplasia (BPH)-like urinary symptoms in patients, was scientifically validated for anti-BPH activity. The ethanolic fruit extract of CS inhibited proliferation of human BPH-stromal cells and the activity was localized to its chloroform-soluble, diterpene-rich fraction. Eight major diterpenes isolated from this fraction exhibited moderate to potent activity and the most active diterpene (labda-8(17),12,14-trien-19-oic acid) exhibited an IC50 of 37.5 μM (antiproliferative activity against human BPH-stromal cells). It significantly inhibited activation (phosphorylation) of Stat-3 in BPH-stromal cells and prevented transactivation of androgen sensitive KLK3/PSA and TMPRSS2 genes in LNCaP cells. Labda-8(17),12,14-trien-19-oic acid-rich CS fraction prevented prostatic hyperplasia in rat model and caused TUNEL labeling of stromal cells with lower expressions of IGF-I, TGF-ß and PCNA, and bcl-2/bax ratio. Human BPH tissues exhibited precise lowering of stromal component after incubation in labda-8(17),12,14-trien-19-oic acid, ex vivo. We conclude that labda-8(17),12,14-trien-19-oic acid contained in CS exhibits anti-BPH activity through inhibition of stromal proliferation and suppression of androgen action in the prostate, presenting a unique lead structure for further optimization of anti-BPH activity.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226 001, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Verma
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.forename: Rajeev
authors.initials: R
authors.lastname: Kumar
authors.forename: Mohammad F
authors.initials: MF
authors.lastname: Khan
authors.forename: Anil K
authors.initials: AK
authors.lastname: Singh
authors.forename: Rolee
authors.initials: R
authors.lastname: Sharma
authors.forename: Kamal R
authors.initials: KR
authors.lastname: Arya
authors.forename: J P
authors.initials: JP
authors.lastname: Maikhuri
authors.forename: Diwakar
authors.initials: D
authors.lastname: Dalela
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D029781:Cupressus / Q000737:chemistry*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology*; D005638:Fruit / Q000737:chemistry; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D000728:Androgens; D004224:Diterpenes; D050796:STAT3 Transcription Factor; C000592291:labda-8(17),12,14-trien-19-oic acid
keywords: BPH; BPH stromal cells; Cupressus; STAT-3; citral; communic acid; diterpene