Enhanced acute apoptotic response to azoxymethane-induced DNA damage in the rodent colonic epithelium by Tyrian purple precursors: a potential colorectal cancer chemopreventative.
Colorectal cancer (CRC) is the second most prevalent and deadly cancer worldwide. Due to the mortality and morbidity associated with chemotherapeutic regimes, research is turning to natural product enhancement of the acute apoptotic response to genotoxic carcinogens (AARGC). Although Tyrian purple dye pigments and precursors from muricid molluscs are known for their anti-proliferative and proapoptotic activity, the chemoprotective properties of these edible molluscs has not been assessed. Enhancement of AARGC by oral administration of muricid extract (ME), containing a mixture of the cytotoxins tyrindoleninone and 6-bromoisatin, was assessed in an azoxymethane (AOM) rodent model. A dose-dependent increase in apoptotic index was observed in the distal colon, with a significant increase detected at an ME dose of 1.0 mg/g (p < 0.01). Proliferation (PCNA) index failed to vary significantly at this ME concentration, which confirms the ME-induced increase in apoptotic response to DNA alkylation. ME also appears to confer no major toxic side effects, as all mice consistently gained weight during the trial and colonic crypt height was maintained (p > 0.05) independent of ME dose. Although, this is the first example of AARGC enhancement by indole-based compounds, bioactive precursor degradation in simulated gastric fluid may prevent introduction of muricids as a chemopreventative food. Nevertheless, the protective effect of ME against CRC in vivo clearly substantiates further research into the chemopreventative efficacy of Muricidae natural products.
School of Biological Sciences, Flinders University, Adelaide, SA, Australia.
Chantel B
CB
Westley
Cassandra M
CM
McIver
Catherine A
CA
Abbott
Richard K
RK
Le Leu
Kirsten
K
Benkendorff
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology / Q000633:toxicity*; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D003106:Colon / Q000187:drug effects*; D015179:Colorectal Neoplasms; D004249:DNA Damage / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011897:Random Allocation; D012377:Rodentia
D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D001397:Azoxymethane