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 |
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Authors: | 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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Affiliation: | 1. Division of Endocrinology, CSIR‐Central Drug Research Institute, , Lucknow, 226 001 India;2. Division of Medicinal and Process Chemistry, CSIR‐Central Drug Research Institute, , Lucknow, 226 001 India;3. Department of Physics and Computer Science, Ewing Christian College, , Allahabad, 211003 India;4. Department of Biotechnology, Integral University, , Lucknow, 226026 India;5. Division of Botany, CSIR‐Central Drug Research Institute, , Lucknow, 226 001 India;6. Department of Urology, CSM Medical University, , Lucknow, 226 003 India |
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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. Copyright © 2014 John Wiley & Sons, Ltd. |
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Keywords: | diterpene BPH Cupressus STAT‐3 communic acid BPH stromal cells citral |
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