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

Vikas Verma, Vikas Sharma, Vishal Singh, Rajeev Kumar, Mohammad F. Khan, Anil K. Singh, Rolee Sharma, Kamal R. Arya, J. P. Maikhuri, Diwakar Dalela, Rakesh Maurya, Gopal Gupta

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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.

Original languageEnglish (US)
Pages (from-to)1196-1203
Number of pages8
JournalPhytotherapy Research
Volume28
Issue number8
DOIs
StatePublished - Aug 2014

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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