TitleCaspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin.
Publication TypeJournal Article
Year of Publication2003
AuthorsG Díaz D, Li Q, Dashwood RH
JournalCancer Res
Date Published2003 Mar 15
KeywordsAlkaline Phosphatase, Anticarcinogenic Agents, Apoptosis, Apoptotic Protease-Activating Factor 1, Cadherins, Caspase 6, Caspase 8, Caspase 9, Caspases, Cell Differentiation, Cell Nucleus, Chlorophyllides, Colonic Neoplasms, Cytochrome c Group, Enzyme Activation, Humans, Intracellular Membranes, Lamins, Membrane Potentials, Mitochondria, Proteins, Proto-Oncogene Proteins c-bcl-2, Tumor Cells, Cultured

Chlorophyllin (CHL), an antimutagenic and anticarcinogenic water-soluble derivative of chlorophyll, was recently found to be highly effective as a chemopreventive agent in a high-risk population exposed unavoidably to aflatoxin B(1) in the diet (P. A. Egner et al., Proc. Natl. Acad. Sci. USA, 98: 14601-14606, 2001). The current study examined the response of HCT116 human colon cancer cells to CHL treatment. Cells exposed to concentrations in the range 0.0625-0.5 mM CHL underwent growth arrest and apoptosis after 24 h, with the formation of a sub-G(1) peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (deltapsi(m)) without the release of cytochrome c or activation of the caspase-9/caspase-3/poly(ADP-ribose) polymerase pathway. However, apoptosis-inducing factor was released from mitochondria into the cytosol and translocated to the nucleus, leading to concentration-dependent cleavage of nuclear lamins. The upstream mediators of this CHL-induced apoptosis pathway were identified as caspase-8/caspase-6 and truncated Bid, acting in conjunction with other proapoptotic members of the Bcl-2 family, such as Bak. These findings suggest that CHL might trigger apoptosis via interaction with putative "death receptors" in the plasma membrane of cancer cells, leading to initial cleavage of procaspase-8 and activation of subsequent downstream events, resulting in the destruction of nuclear lamins. Importantly, E-cadherin and alkaline phosphatase, which are indicators of cell differentiation, were strongly induced at all concentrations of CHL. Thus, in addition to being an effective blocking agent during the initiation phase, these findings support a role for CHL as a suppressing agent and as a possible novel therapeutic strategy directed toward aberrant cell proliferation in the colon.

Alternate JournalCancer Res.
PubMed ID12649185
Grant ListR01 CA080176-03 / CA / NCI NIH HHS / United States
P30 ES00210 / ES / NIEHS NIH HHS / United States
CA80176 / CA / NCI NIH HHS / United States
R01 CA065525-08 / CA / NCI NIH HHS / United States
R01 CA080176-02 / CA / NCI NIH HHS / United States
R01 CA065525-09 / CA / NCI NIH HHS / United States
R01 CA080176-05 / CA / NCI NIH HHS / United States
CA65525 / CA / NCI NIH HHS / United States
R01 CA065525-07 / CA / NCI NIH HHS / United States
R01 CA080176-04 / CA / NCI NIH HHS / United States
R01 CA065525-06A1 / CA / NCI NIH HHS / United States