Anti colon cancer components from Lebanese sage (Salvia libanotica) essential oil: Mechanistic basis.

Lebanese sage essential oil possesses antitumor properties, however, the bioactive components and antitumor mechanisms are not known. Here we show that combining the three sage bioactive compounds, Linalyl acetate (Ly), Terpeniol (Te) and Camphor (Ca), caused synergistic inhibition of the growth of two isogenic human colon cancer cell lines HCT-116 (p53(+/+) and p53(-/-)) and had no effect on growth of FHs74Int normal human intestinal cell line. In p53(+/+) cells, the combination of Ly + Te + Ca (10(-3) M of each) caused significant accumulation of cells in PreG(1) (64% at 48 hours); less preG(1) increase was observed in response to Ly + Te (25%) or Ly + Ca (14%). In p53(-/-) cells, Ly + Te + Ca caused cell accumulation in PreG(1) and G(2)/M phases. In response to the three components, 58% apoptosis occurred in p53(+/+) cells and 38% in p53(-/-) cells. Apoptosis by Ly + Te + Ca, in p53+/+ cells, was associated with increased Bax/Bcl-2 ratio and pp53/p53 ratio, cleavage and activation of caspase-3, loss of mitochondrial membrane potential and cytochrome c release. In p53(-/-) cells, the disruption of mitochondrial membrane potential was observed but to a lesser extent than in p53(+/+) cells and caspase activation or cleavage did not appear to be involved in drug-induced apoptosis. Sage components induced poly(ADP-ribose)-polymerase (PARP) cleavage in both p53(+/+) and p53(-/-) cell lines. Pretreatment with the caspase-3 inhibitor and pan caspase inhibitor abrogated drug-mediated apoptosis and blocked procaspase-3 activation and partially blocked PARP cleavage in p53(+/+) cells. Conversely, in p53(-/-) cells, pre-incubation with caspase inhibitors potentiated drug-induced cell death. It appears that apoptosis in p53(+/+) cells is through the mitochondrial-mediated, caspase-dependent pathway, while in p53(-/-) cells apoptosis is mostly caspase independent despite the presence and features indicating caspase-dependent cell death, such as cytochrome c release and PARP cleavage. Our findings encourage further studies of sage oil components as promising chemotherapeutic agents against colon cancer.

Assessment of drug activity and proliferation ex vivo for prediction of outcome in aggressive non-Hodgkin's lymphomas.

The activity of cytotoxic drugs and tumour cell proliferation rate were assessed ex vivo using the fluorometric microculture cytotoxicity assay (FMCA) and stainings for Ki67 and mitosis in 40 patients with aggressive non-Hodgkin's lymphomas (NHL). The findings were correlated to clinical response and survival. Twenty-three patients had a complete remission and 10 a partial remission. A drug sensitivity index based on the cell survival for three major drugs in NHL treatment was derived empirically and proliferation was expressed as low-, intermediate- or high. In 5 out of 8 drugs tested, cell survival ex vivo was higher in clinical non-responders than that in responders. Using the median drug sensitivity index as a cut-off, the sensitivity and specificity for tumour response were 58% and 100%, respectively, and was similar for the proliferation index. Both indices combined increased the sensitivity to 73% at retained specificity. Intermediate/high proliferation was significantly associated with impaired survival, whereas the drug sensitivity index was not predictive of survival. Thus, ex vivo assessments of drug sensitivity and proliferation seem to provide prognostic information in aggressive NHL.