Bonnie Nolan

Voluntary exercise inhibits intestinal tumorigenesis in ApcMin/+ mice and azoxymethane/dextran sulfate sodium-treated mice

BackgroundEpidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, ApcMin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice.MethodsIn Experiments 1 and 2, five-week old female ApcMin/+ mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks.ResultsIn the ApcMin/+ mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In ApcMin/+ mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear β-catenin levels, but increased E-cadherin levels in the tumors.ConclusionThese results indicate hat voluntary exercise inhibited intestinal tumorigenesis in ApcMin/+ mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism.

Stimulatory effect of voluntary exercise or fat removal (partial lipectomy) on apoptosis in the skin of UVB light-irradiated mice.

Earlier studies indicated that high dietary fat and obesity are associated with an increased risk of cancer at several organ sites in experimental animals and in humans. In a recent study we found that voluntary running wheel exercise decreased body fat and inhibited ultraviolet B light (UVB)-induced carcinogenesis in the epidermis of SKH-1 mice. In the present study we demonstrate that voluntary running wheel exercise stimulated UVB-induced apoptosis in the epidermis by a p53-independent mechanism, and voluntary exercise also stimulated apoptosis in UVB-induced tumors in tumor-bearing mice. Exercise had no effect in non-UVB-treated epidermis or in areas of the epidermis away from tumors in tumor-bearing mice. In addition, we found that removal of the parametrial fat pads (partial lipectomy) 2 weeks before UVB irradiation enhanced UVB-induced apoptosis. The results of our studies suggest that fat cells secrete substances that inhibit apoptosis in cells with DNA damage and possibly also in tumors. Our results help explain why exercise or various dietary regimens that decrease tissue fat inhibit carcinogenesis.

Voluntary exercise together with oral caffeine markedly stimulates UVB light-induced apoptosis and decreases tissue fat in SKH-1 mice.

Treatment of SKH-1 mice orally with caffeine (0.1 mg/ml in the drinking water), voluntary running wheel exercise, or a combination of caffeine and exercise for 2 weeks (i) decreased the weight of the parametrial fat pads by 35, 62, and 77%, respectively; (ii) decreased the thickness of the dermal fat layer by 38, 42, and 68%, respectively; (iii) stimulated the formation of UVB-induced apoptotic sunburn cells in the epidermis by 96, 120, and 376%, respectively; and (iv) stimulated the formation of UVB-induced caspase 3 (active form)-positive cells in the epidermis by 92, 120, and 389%, respectively (average of two experiments). Oral administration of caffeine (0.4 mg/ml in the drinking water) in combination with voluntary exercise was less effective than administration of the low dose of caffeine in combination with exercise in stimulating UVB-induced apoptosis. Although orally administrated caffeine (0.1 mg/ml in the drinking water) or voluntary exercise for 2 weeks caused only a small nonsignificant stimulation of UVB-induced increase in the percentage of phospho-p53 (Ser-15)-positive cells in the epidermis (27 or 18%, respectively), the combination of the two treatments enhanced the UVB-induced increase in phospho-p53 (Ser-15)-positive cells by 99%. The plasma concentration of caffeine in mice ingesting caffeine (0.1–0.4 mg/ml drinking water) is similar to that in the plasma of most coffee drinkers (one to four cups per day). Our studies indicate a greater than additive stimulatory effect of combined voluntary exercise and oral administration of a low dose of caffeine on UVB-induced apoptosis.

Oral caffeine during voluntary exercise markedly inhibits skin carcinogenesis and decreases inflammatory cytokines in UVB-treated mice

Ultraviolet B (UVB)-pretreated SKH-1 mice were treated with water, caffeine (0.1 mg/ml), voluntary running wheel exercise (RW) or caffeine together with RW for 14 wk. Treatment of the mice with caffeine, RW, or caffeine plus RW decreased skin tumors per mouse by 27%, 35%, and 62%, respectively, and the tumor volume per mouse was decreased by 61%, 70%, and 85%, respectively. In mechanistic studies, mice were treated with water, caffeine, RW, or caffeine plus RW for 2 wk prior to a single irradiation with UVB. Caffeine plus RW increased RW activity by 22% when compared with RW alone. Caffeine ingestion was not significantly different between groups. Treatment of mice with caffeine plus RW for 2 wk decreased the weight of the parametrial fat pads and stimulated the formation of UVB-induced apoptosis to a greater extent than treatment with caffeine or RW alone. An antibody array revealed that caffeine plus RW administered to mice fed a high-fat diet and irradiated with UVB decreased the epidermal levels of lipopolysaccharide-induced CXC chemokine, soluble TNF alpha receptor-1, and macrophage inflammatory protein-1γ. Overall, caffeine during RW exerts a stronger effect than either treatment alone for decreasing tissue fat, increasing UVB-induced apoptosis, lowering the levels of cytokines associated with inflammation and for inhibiting UVB-induced carcinogenesis.

Oral administration of caffeine during voluntary exercise markedly decreases tissue fat and stimulates apoptosis and cyclin B1 in UVB-treated skin of hairless p53-knockout mice

Treatment of p53(-/-) mice orally with caffeine, voluntary exercise or their combination for 2 weeks prior to a single irradiation with UVB (i) decreased the weight of the epididymal fat pads by 22, 40 and 56%, (ii) decreased the thickness of the dermal fat layer by 10, 26 and 42%, (iii) increased the number of apoptotic sunburn cells by 29, 100 and 489%, (iv) increased the number of caspase-3-positive cells by 33, 117 and 667% and (v) increased the number of mitotic cells with cyclin B1-positive staining by 40, 210 and 510%, respectively. Pearsons correlation coefficient indicated a statistically significant inverse relationship between the level of tissue fat and the number of mitotic cells with cyclin B1 in p53(-/-) mice but not in p53(+/+) littermates. Western blot analysis indicated that treatment of p53(-/-) mice with caffeine together with exercise increased the level of cyclin B1 significantly more than in p53(+/+) mice. p53(-/-) mice, but not p53(+/+) mice, treated with caffeine during exercise exhibited a dramatic decrease in the level of survivin. Our results suggest that voluntary exercise in combination with oral caffeine may exert a synergistic increase in UVB-induced apoptosis and that tissue fat may be a more important modulator of apoptosis and carcinogenesis in p53-deficient mice than in p53-normal mice. The stimulatory effects on apoptosis in p53(-/-) mice by the combination treatment might be associated with increased levels of cyclin B1 and decreased levels of survivin.

Abstract 4286: Oral caffeine during voluntary exercise markedly inhibits skin carcinogenesis and decreases cytokines associated with inflammation in UVB-treated mice

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL In previous studies, we found that treatment of female SKH-1 mice with either oral administration of caffeine or voluntary running wheel exercise (RW) inhibited the formation of UVB-induced skin tumors. In the present study, we determined whether RW in combination with oral caffeine has a synergistic inhibitory effect on UVB-induced skin carcinogenesis. UVB-pretreated female high-risk SKH-1 mice (7-8 weeks of age, total 160 mice) have no tumors but they develop tumors in the absence of further UVB irradiation over the next several months. These high-risk mice (40 mice per group) were then treated with water (control), caffeine (0.1 mg/ml in drinking fluid), RW or caffeine together with RW for 14 weeks. Although there were no differences in body weight between the four groups during the course of the study, treatment with caffeine increased running wheel activity by 40% when compared with RW alone. Treatment of the mice with caffeine, RW or caffeine together with RW decreased skin tumors per mouse by 27, 35 and 62%, respectively, and the tumor volume per mouse was decreased by 61, 70 and 85%, respectively. In mechanistic studies, female SKH-1 mice were treated with water (control), caffeine (0.1 mg/ml), RW, or a combination of caffeine plus RW for 2 weeks. All mice were then exposed to a single dose of UVB (30 mJ/cm2) and sacrificed before (control) and at 0.1, 0.5, 1, 2, 4, 6, 10, 16, 24, and 48 h post UVB. The results showed that mice treated with oral caffeine for 2 weeks increased RW activity by 22% when compared with the mice treated with RW alone. Treatment of mice orally with caffeine, RW, or a combination of caffeine and RW for 2 weeks (a) decreased the weight of the parametrial fat pads by 30, 56 and 63%, respectively, (b) stimulated the formation of UVB-induced apoptotic sunburn cells in the epidermis by 21, 124 and 298% at 6 hours post-UVB, and stimulated the formation of UVB-induced caspase 3 (active form) positive cells in the epidermis by 30, 164 and 333%, respectively at 6 hours post-UVB. Combination treatment of the mice had a small but significant inhibitory effect on cell proliferation as measured by bromodeoxyuridine incorporation into DNA in the epidermis. Antibody array with 40 cytokines associated with inflammation revealed that oral caffeine together with RW administered to mice fed a high fat diet rich in omega-6 fatty acids for 2 weeks significantly decreased the UVB-induced increases in the levels of LIX, sTNF R1 and MIP-1α as well as several other cytokines associated with inflammation. Our results indicate that voluntary exercise in combination with oral caffeine exerts a stronger effect than either treatment alone for decreasing tissue fat, increasing UVB-induced apoptosis, lowering the levels of cytokines associated with inflammation and for inhibiting UVB-induced carcinogenesis in UVB-pretreated high-risk mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4286. doi:1538-7445.AM2012-4286