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@ARTICLE{Daaboul:128678,
      author       = {H. E. Daaboul and C. F. Daher and R. I. Taleb and J. Boulos
                      and K. Bodman-Smith and P. Boukamp$^*$ and W. N. Shebaby and
                      C. Dagher and M. El-Sibai and M. A. Mroueh},
      title        = {β-2-himachalen-6-ol protects against skin cancer
                      development in vitro and in vivo.},
      journal      = {Journal of pharmacy and pharmacology},
      volume       = {69},
      number       = {11},
      issn         = {0022-3573},
      address      = {Wallingford, Oxon},
      publisher    = {Pharmaceutical Press64910},
      reportid     = {DKFZ-2017-04693},
      pages        = {1552 - 1564},
      year         = {2017},
      abstract     = {Previous studies in our laboratory showed that Daucus
                      carota oil extract (DCOE) possesses remarkable in-vitro
                      anticancer activity and antitumour promoting effect against
                      DMBA/TPA skin carcinogenesis in mice. Chemical analysis of
                      DCOE led to the isolation of the β-2-himachalen-6-ol (HC),
                      major sesquiterpene with a potent anticancer activity
                      against various colon, breast, brain and skin cancer cells.
                      This study investigated the anticancer activity of HC
                      against invasive epidermal squamous cell carcinoma cells and
                      evaluated its effect in a DMBA/TPA skin carcinogenesis
                      Balb/c murine model.HaCaT-ras II-4 epidermal squamous cells
                      were treated with HC (1, 5, 10, 25 and 50 μg/ml), and cell
                      viability was evaluated with WST 1 assay kit. Cell cycle
                      analysis was carried out by flow cytometry, and
                      pro/anti-apoptotic proteins were measured using Western
                      blot. The effect of topical and intraperitoneal (IP)
                      treatment with HC in mice was assessed using the
                      DMBA/TPA skin carcinogenesis model. Cisplatin (2.5 mg/kg;
                      IP) was used as a positive control. Papilloma incidence,
                      yield and volume were monitored, and isolated papillomas
                      were assessed for their pro/anti-apoptotic proteins and
                      morphology.β-2-himachalen-6-ol showed a dose-dependent
                      decrease in cell survival with an IC50 and IC90 of 8 and
                      30 μg/ml, respectively. Flow cytometry analysis revealed
                      that treatment with 10 μg/ml HC significantly increased
                      the number of cells undergoing late apoptosis $(28\%),$
                      while 25 μg/ml caused a larger cell shift towards late
                      apoptosis $(46.6\%)$ and necrosis $(39\%).$ A significant
                      decrease in protein levels of p53 and Bcl-2 and a
                      significant increase in p21 and Bax were observed. Also,
                      there was a significant decrease in p-Erk and p-Akt protein
                      levels. The treatment of mice (IP and topical) with HC
                      caused a significant decrease in papilloma yield, incidence
                      and volume. Similar effects were observed with cisplatin
                      treatment, but HC-treated groups exhibited twofold to
                      threefold increase in survival rates. Similar patterns in
                      the pro- and anti-apoptotic proteins were observed in mice
                      treated with HC, except for a significant increase in p53
                      protein.In conclusion, HC treatment induced cell cycle
                      arrest (low dose) and promoted apoptosis partly via
                      inhibition of the MAPK/ERK and PI3K/AKT pathways with no
                      significant toxicity to laboratory mice.},
      cin          = {A110},
      ddc          = {610},
      cid          = {I:(DE-He78)A110-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28872682},
      doi          = {10.1111/jphp.12796},
      url          = {https://inrepo02.dkfz.de/record/128678},
}