Sirolimus and Metformin Synergistically Inhibits Colon Cancer In Vitro and In Vivo

• Published in: Journal of Korean medical science 2017, 32(9), 231, pp.1385-1395
• Main Authors: Mussin, Nadiar, Oh, Seung Cheol, Lee, Kwang Woong, Park, Min Young, Seo, Sooin, Yi, Nam Joon, Kim, Hyeyoung, Yoon, Kyung Chul, Ahn, Sung Woo, Kim, Hyo Sin, Hong, Suk Kyun, Oh, Dong Kyu, Suh, Kyung Suk
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Cyclosporine - pharmacology; Cyclosporine - therapeutic use; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; HCT116 Cells; HT29 Cells; Humans; Metformin - pharmacology; Metformin - therapeutic use; Mice; Mice, Inbred BALB C; Mice, Nude; Original; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction - drug effects; Sirolimus - pharmacology; Sirolimus - therapeutic use; Smad3 Protein - metabolism; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Transplantation, Heterologous; 의학일반
• ISSN: 1011-8934; 1598-6357
• DOI: 10.3346/jkms.2017.32.9.1385

We estimated the effect of various immunosuppressants (ISs) and metformin (M) to provide theoretical background of optimal therapeutic strategy for de novo colon cancer after liver transplantation (LT). Three colon cancer cell lines (HT29, SW620, and HCT116) were used in in vitro studies. HT29 was also used in BALB/c-nude mice animal models. Following groups were used in both in vitro and in vivo studies: sirolimus (S), tacrolimus (T), cyclosporin A (CsA), M, metformin/sirolimus (Met/S), metformin/tacrolimus (Met/T), and metformin/cyclosporin A (Met/CsA). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed and western blot analyses were performed for mTOR pathway proteins, apoptosis proteins, and epithelial-mesenchymal-transition (EMT) proteins. Tumor volume was measured for 4 weeks after inoculation. MTT-assay revealed significant cell viability inhibition in all 3 colon cancer cell lines in groups of S, M, and Met/S. Of note, group Met/S showed synergistic effect compare to M or S group. Western blot analysis showed significant low levels of all investigated proteins in groups of S and Met/S in both in vitro and in vivo experiment. Tumor growth was significantly inhibited only in the Met/S group. Combination of Met and S showed the most potent inhibition in all colon cancer cell lines. This finding might have application for de novo colon cancer.