Dataset Information

Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-Induced Colon Cancer in F344 Rat Model.

ABSTRACT: Recent observational studies suggest that bisphosphonates (BP) and antidiabetic drugs are associated with colorectal cancer risk reduction. Hence, we evaluated the colorectal cancer preventive effects of BPs (zometa and fosamax), individually and when combined with metformin, in azoxymethane-induced rat colon cancer model. Rat (30/group) were randomized and treated subcutaneously with azoxymethane to induce colorectal cancer. Dietary intervention with zometa or fosamax (0, 20, or 100 ppm) or metformin (1,000 ppm) or the combinations (zometa/fosamax 20 ppm plus metformin 1,000 ppm) began 4 weeks after azoxymethane treatment, at premalignant lesions stage. Rats were killed 40 weeks post drug intervention to assess colorectal cancer preventive efficacy. Dietary zometa (20 ppm) inhibited noninvasive adenocarcinomas multiplicity by 37% (P < 0.03) when compared with control diet fed group. Fosamax at 20 ppm and 100 ppm significantly reduced adenocarcinoma incidence (P < 0.005) and inhibited the noninvasive adenocarcinoma multiplicities by 43.8% (P < 0.009) and 60.8% (P < 0.004), respectively, compared with the group fed control diet. At 1,000 ppm dose, metformin failed to suppress colon adenocarcinoma formation. However, the lower dose combinations of zometa or fosamax with metformin resulted in significant inhibition of noninvasive adenocarcinoma by 48% (P < 0.006) and 64% (P < 0.0002), and invasive adenocarcinoma by 49% (P < 0.0005) and 38% (P < 0.006), respectively. Biomarker analysis of combination drug-treated tumors showed a decrease in cell proliferation with increased apoptosis when compared with untreated tumors. Overall, our results suggest that the combination of low doses of zometa or fosamax with metformin showed synergistic effect and significantly inhibited colon adenocarcinoma incidence and multiplicity.

SUBMITTER: Madka V

PROVIDER: S-EPMC7007371 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-Induced Colon Cancer in F344 Rat Model.

Madka Venkateshwar V Kumar Gaurav G Pathuri Gopal G Zhang Yuting Y Lightfoot Stanley S Asch Adam S AS Mohammed Altaf A Steele Vernon E VE Rao Chinthalapally V CV

Cancer prevention research (Philadelphia, Pa.) 20191107 2

Recent observational studies suggest that bisphosphonates (BP) and antidiabetic drugs are associated with colorectal cancer risk reduction. Hence, we evaluated the colorectal cancer preventive effects of BPs (zometa and fosamax), individually and when combined with metformin, in azoxymethane-induced rat colon cancer model. Rat (30/group) were randomized and treated subcutaneously with azoxymethane to induce colorectal cancer. Dietary intervention with zometa or fosamax (0, 20, or 100 ppm) or met ...[more]

PMID: 31699708

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Project description:Gut microbiota, an important component that affects host health, change rapidly and directly in response to altered diet composition. Recently, the role of diet-microbiome interaction on the development of colon cancer has been the focus of interest. Colon cancer occurs more frequently in an aged population, and in males. However, the effect of dietary changes on the gut microbiome has been studied mainly in young males, even though it may vary with age and sex. The aim of this study was to investigate microbial changes and host response in the colons of male and female 6-week-old (young) and 2-year-old (old) Fisher-344 rats exposed to a high-fat diet (HFD). Our results showed that exposure to HFD for 8 weeks decreased the species richness of microbiota (Chao1) and increased Firmicutes/Bacteroidetes ratio only in aged rats, and not in young rats. Sex differences underlying the alteration by HFD in the gut microbiome were observed in the microbiome of aged rats. For instance, the abundance ratio of Akkermansia muciniphila and Desulfovibrio spp. increased in response to HFD in young rats and female aged rats, but not in male aged rats. Histological inflammation and cell proliferation of colon mucosa (indexed by Ki67) were significantly increased by HFD even in young rats; aged rats showed significantly higher cell proliferation in the HFD group than in the control. The HFD-induced decrease of species richness and the increase in specific species (Desulfovibrio spp. and Clostridium lavalense), which produce carcinogenic compounds such as H2S and N-nitroso compounds, were significantly correlated with Ki67 index. In colon mucosa, the concentration of myeloperoxidase was increased by HFD only in males, and not in females. In conclusion, the results suggest a link between HFD-induced gut dysbiosis (particularly the low species richness and high abundance ratios of Desulfovibrio spp. and C. lavalense) and cell proliferation of colon mucosa (indicated by Ki67 IHC). In addition, sex differences influence the response of gut microbiome to HFD particularly in old age. Such sex differences in the gut microbiota might be related to sex differences in inflammation in the colon mucosa.

Dataset Information

Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-Induced Colon Cancer in F344 Rat Model.

Publications

Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-Induced Colon Cancer in F344 Rat Model.

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