The aim of this work was to characterize the antitumoral activity of the plant compound
7-epi-nemorosone in prostate
carcinoma cell lines.
Prostate cancer is the most frequently diagnosed
malignancy and the second-leading cause of
cancer death in men. In spite of the current therapeutic options for this
cancer entity, many patients die due to
metastases in distant organs and acquired
chemotherapy resistance. Thus, approaches to provide improvements in outcome and quality of life for such patients are urgently needed. Recently, the polyisoprenylated
benzophenone 7-epi-nemorosone, originally collected by honeybees from Clusia rosea and Clusia grandiflora (Clusiaceae), has been described to be a potent antitumoral agent. Here, its activity in prostate
carcinoma is reported.
7-epi-nemorosone was isolated from Caribbean
propolis employing RP-HPLC techniques. Its cytotoxicity was assessed using the MTT proliferation assay in human
androgen-dependent prostate
carcinoma LNCaP cells including an MDR1(+) sub-line. No cross-resistance was detected. FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1, G1, and depletion in the S phase populations. A concomitant down-regulation of
cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot.
Annexin-V-FITC labeling and
caspase-3 cleavage assays showed that
7-epi-nemorosone induced apoptotic events. Major signal transduction elements such as
p38 MAPK and Akt/PKB as well as
androgen receptor AR and PSA production were found to be down-regulated after exposure to the
drug. ERK1/2
protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream
kinases MEK1/2. Additionally, Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2. Here, we demonstrate for the first time that
7-epi-nemorosone exerts cytotoxicity in an
androgen-dependent prostate
carcinoma entity by targeting the MEK1/2 signal transducer.