Abstract A14: Chemopreventive efficacy of bisphosphonates, Zometa and Fosamax, alone or in combination with metformin in AOM-induced rat colon cancer model

Abstract

Abstract Colorectal cancer (CRC) is a major public health issue world-wide with an estimated 600,000 deaths annually and increasing case incidences. Clinical observational studies suggest that osteoporosis drugs (Zometa and Fosamax) and anti-diabetes drug (Metformin) are associated with risk reduction of several cancers, including CRC. In the present study, we assessed the chemopreventive properties of bisphosphonates, Zometa and Fosamax, individually as well as in combination with Metformin, against azoxymethane (AOM)-induced colon cancers. Rat (30 animals per group) colon cancers were induced by two weekly doses of AOM, by s.c. Four weeks after AOM treatment, rats were fed experimental diets containing Zometa or Fosamax (0, 20 or 100 ppm), 1,000 ppm metformin or their low dose combination (20 ppm) with Metformin (1,000ppm). All rats were euthanized 44 weeks after AOM treatment and assessed for colon tumor efficacy and various biomarkers in colonic tissues. Long-term chronic administration of Zometa, Fosamax, metformin or combinations does not show any overt-toxicities in rats. Administration of Zometa significantly suppressed AOM-induced noninvasive adenocarcinomas multiplicity by 37% (p<0.03) and had no significant (p>0.05) effect on invasive adenocarcinoma multiplicity. Dietary Fosamax at 20 ppm and 100 ppm inhibited the noninvasive colon adenocarcinoma multiplicities by 43.8% (p<0.009) and 60.8% (p<0.004), respectively, as compared to control diet fed group; however, Fosamax failed to show any significant effect on the invasive carcinoma multiplicity. Also, Fosamax administration significantly suppressed AOM-induced noninvasive adenocarcinoma incidence (p<0.005). Metformin administered at 1,000 ppm in diet failed to show any inhibitory effect on colon adenocarcinomas multiplicity or incidence. Importantly, low-dose combination of Zometa or Fosamax (20ppm) with 1,000 ppm Metformin significantly suppressed noninvasive adenocarcinomas by 48% (p<0.006) and 64% (p<0.0002), and invasive adenocarcinomas by 49% (p<0.0005) and 38% (p<0.006), respectively. Also, Combination of Zometa or Fosamax with metformin significantly suppressed noninvasive and invasive adenocarcinoma formation and tumor volumes (>38%, p<0.01). In tumors of rats fed combination of Zometa or Fosamax with metformin diets, there was a significant decrease in markers of proliferation (PCNA, β-catenin, VEGF) and increase in apoptosis (p53, p21, Annexin V) when compared with colonic tumors of rats fed the control diet. Overall, our results suggest that bisphosphonates had significant inhibitory effect on AOM-induced noninvasive (intramucosal) carcinomas, but had limited effect on total adenocarcinomas and notably, combination of low doses of Zometa or Fosamax with metformin had shown synergistic colon adenocarcinoma inhibitory effects. Further studies are warranted to explore the combination of metformin and bisphosphonates for colon cancer prevention. {This work was supported by NCI-CN-53300} Citation Format: Venkateshwar Madka, Yuting Zhang, Misty Brewer, Li Qian, Altaf Mohammed, Stan Lightfoot, Vernon E. Steele, Levy Kopelovich, Chinthalapally V. Rao. Chemopreventive efficacy of bisphosphonates, Zometa and Fosamax, alone or in combination with metformin in AOM-induced rat colon cancer model. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A14.