title: Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy.
abstract: Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs), and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1) the signaling heterogeneity of CRC cell populations, and (2) the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis-enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589) with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation). The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract). Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon.
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bordonaro
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Drago
authors.affiliation: California Northstate University, College of Medicine, 9700 West Taron Drive, Elk Grove, CA 95757, United States of America.
authors.forename: Wafa
authors.initials: W
authors.lastname: Atamna
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, United States of America.
authors.forename: Darina L
authors.initials: DL
authors.lastname: Lazarova
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019587:Dietary Supplements; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D000077767:Panobinostat; D011429:Propolis / Q000008:administration & dosage; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011429:Propolis; D000077767:Panobinostat