Bisphosphonates Zometa and Fosamax Synergize with Metformin to Prevent AOM-induced Colon Cancer in F344 Rat Model
Menée à l'aide de modèles murins de cancers du côlon induits par l'azoxyméthane, cette étude analyse les propriétés chimiopréventives des bisphosphonates Zometa et Fosamax, individuellement ou en association avec la metformine
Clinical observational studies suggest that bisphosphonates and anti-diabetes drugs are associated with risk reduction for colorectal cancer. We assessed the chemopreventive properties of bisphosphonates Zometa and Fosamax, individually or in combination with metformin, against azoxymethane (AOM)-induced colon cancers. Rat (30/group) colon cancers were induced by AOM. Four weeks after AOM treatment, rats were fed experimental diets containing Zometa or Fosamax (0, 20, or 100 ppm), metformin (1,000 ppm), or the bisphosphonates in combination (20 ppm) with metformin (1,000 ppm). All rats were euthanized 45 weeks after AOM treatment and assessed for colon tumor efficacy and various biomarkers in colonic tissues. Administration of Zometa (20 ppm) suppressed AOM-induced non-invasive adenocarcinomas multiplicity by 37% (p<0.03). Fosamax at 20 ppm and 100 ppm significantly inhibited the non-invasive adenocarcinoma multiplicities by 43.8% (p<0.009) and 60.8% (p<0.004), respectively, and reduced adenocarcinoma incidence (p<0.005), compared with the group fed control diet. Metformin had no inhibitory effect on colon adenocarcinomas. Importantly, a low-dose combination of 20 ppm of Zometa or Fosamax with metformin significantly suppressed multiplicity of noninvasive adenocarcinoma by 48% (p<0.006) and 64% (p<0.0002), and invasive adenocarcinomas by 49% (p<0.0005) and 38% (p<0.006), respectively. In tumors of rats fed a combination of Zometa or Fosamax with metformin diets, there was a significant decrease in markers of proliferation and increased apoptosis. 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.