This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Díaz, G. D. Articles by Dashwood, R. H. Search for Related Content PubMed PubMed Citation Articles by Díaz, G. D. Articles by Dashwood, R. H.

Caspase-8 and Apoptosis-inducing Factor Mediate a Cytochrome c-independent Pathway of Apoptosis in Human Colon Cancer Cells Induced by the Dietary Phytochemical Chlorophyllin¹

Linus Pauling Institute [G. D. D., Q. L., R. H. D.] and Department of Environmental and Molecular Toxicology [R. H. D.], Oregon State University, Corvallis, Oregon 97331

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 B₁ 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-G₁ peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (_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.

This article has been cited by other articles:

				M. H. Kang, Z. Wan, Y. H. Kang, R. Sposto, and C. P. Reynolds Mechanism of Synergy of N-(4-Hydroxyphenyl)Retinamide and ABT-737 in Acute Lymphoblastic Leukemia Cell Lines: Mcl-1 Inactivation J Natl Cancer Inst, April 16, 2008; 100(8): 580 - 595. [Abstract] [Full Text] [PDF]

				C.-C. Su, Y.-P. Lin, Y.-J. Cheng, J.-Y. Huang, W.-J. Chuang, Y.-S. Shan, and B.-C. Yang Phosphatidylinositol 3-Kinase/Akt Activation by Integrin-Tumor Matrix Interaction Suppresses Fas-Mediated Apoptosis in T Cells J. Immunol., October 1, 2007; 179(7): 4589 - 4597. [Abstract] [Full Text] [PDF]

				M. H. Kang, Y. H. Kang, B. Szymanska, U. Wilczynska-Kalak, M. A. Sheard, T. M. Harned, R. B. Lock, and C. P. Reynolds Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo Blood, September 15, 2007; 110(6): 2057 - 2066. [Abstract] [Full Text] [PDF]

				J. Mohan, A. A. Gandhi, B. C. Bhavya, R. Rashmi, D. Karunagaran, R. Indu, and T. R. Santhoshkumar Caspase-2 Triggers Bax-Bak-dependent and -independent Cell Death in Colon Cancer Cells Treated with Resveratrol J. Biol. Chem., June 30, 2006; 281(26): 17599 - 17611. [Abstract] [Full Text] [PDF]

				M. C. Myzak, K. Hardin, R. Wang, R. H. Dashwood, and E. Ho Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells Carcinogenesis, April 1, 2006; 27(4): 811 - 819. [Abstract] [Full Text] [PDF]

				O. Carter, G. S. Bailey, and R. H. Dashwood The Dietary Phytochemical Chlorophyllin Alters E-Cadherin and {beta}-Catenin Expression in Human Colon Cancer Cells- J. Nutr., December 1, 2004; 134(12): 3441S - 3444S. [Abstract] [Full Text] [PDF]