Effects of propolis and gamma‐cyclodextrin on intestinal neoplasia in normal weight and obese mice

Abstract

Obesity is associated with colorectal cancer (CRC). This effect might be attributed to adipokine‐supported signaling. We have established that propolis suppresses survival signaling in CRC cells in vitro; therefore, we ascertained the ability of a propolis supplement to modulate intestinal neoplastic development in C57BL/6J‐ApcMin/+/J mice in the lean and obese state. To induce obesity, mice were fed with a Western diet containing 40% fat. Since the propolis supplement includes gamma‐cyclodextrin, the interventions included diets supplemented with or without gamma‐cyclodextrin. The animals were administered the following diets: (1) control diet, (2) control diet/gamma‐cyclodextrin, (3) control diet/propolis, (4) Western diet, (5) Western diet/gamma‐cyclodextrin, and (6) Western diet/propolis. Western diet, resulting in obesity, accelerated neoplastic progression, as evidenced by the larger size and higher grade dysplasia of the neoplasms. In the context of normal weight, gamma‐cyclodextrin and propolis affected neoplastic progression, as determined by the size of the lesions and their grade of dysplasia. A statistically significant decrease in the number of adenomas was detected in mice fed a control diet with the propolis supplement (61.8 ± 10.6 vs. 35.3 ± 7.6, P = 0.008). Although there was no significant difference in the polyp numbers between the six groups, the mice with the lowest number and size of adenomas were those fed a Western diet with gamma‐cyclodextrin. This unexpected outcome might be explained by the increased levels of apoptosis detected in the intestinal tissues of these obese mice. We posit that butyrate derived from the metabolism of gamma‐cyclodextrin may contribute to the decreased neoplastic burden in the context of obesity; however, future studies are required to address this possibility.

Hypothesis: Induction of biomarkers for detection of colonic neoplasms

“…This apoptotic activity of gCD would impact both neoplastic initiation (number of lesions) and progression (size of lesions). In agreement with this possibility, we have detected a decrease in the average size and number of lesions in Apc Min mice exposed to diets containing gCD, and the differences were statistically significant in the context of Western diets 6 . The ability of gCD to induce apoptosis was supported by our findings that the levels of the pro-apoptotic protein Bax and the cleaved Caspase 3 (a hallmark of apoptosis) were increased in intestinal tissues of mice on a Western diet with gCD 6 .…”

“…In agreement with this possibility, we have detected a decrease in the average size and number of lesions in Apc Min mice exposed to diets containing gCD, and the differences were statistically significant in the context of Western diets 6 . The ability of gCD to induce apoptosis was supported by our findings that the levels of the pro-apoptotic protein Bax and the cleaved Caspase 3 (a hallmark of apoptosis) were increased in intestinal tissues of mice on a Western diet with gCD 6 . Among Apc Min mice with normal weight, the propolis supplement (containing 6% gCD) more effectively reduced neoplastic burden 6 .…”

“…Mutations in APC are gatekeeping mutations in almost 80% of all sporadic human CC cases; however, there is evidence that additional (mostly passenger) mutations accumulate at even early stages of neoplastic development. We have established that intestinal adenoma development in Apc Min mice is characterized by multiple, albeit highly variable, types of mutations 6 . We have sequenced the neoplastic exomes of five normal weight and five obese mice.…”

“…The effect of gCD on intestinal neoplastic burden in mice 6 could be explained by the metabolism of gCD to butyrate, as this short-chain fatty acid induces apoptosis in neoplastic intestinal cells. This apoptotic activity of gCD would impact both neoplastic initiation (number of lesions) and progression (size of lesions).…”

“…All of these changes can be registered by comparative analyses of sera before and after administration of dietary supplements, with the objective of detecting colonic neoplasms. Based upon our previous studies 6 , we propose that gamma-cyclodextrin (gCD) and propolis induce biomarkers (e.g., neoplastic proteins, apoptotic markers, immune response proteins, metabolites) that are released in the systemic circulation, and the pattern and level of expression of the markers correlate with the presence or absence of intestinal neoplasms.…”