Background: Colorectal cancer is the third most common cancer in incidence and cause of death in the United States. The current treatment modalities include chemotherapy, radiation, and surgery. Many people are genetically predisposed for colon cancer through mutations in genes such as adenomatous polyposis coli (APC). While the absence of APC causes aberrant Wnt/Beta catenin signaling, the APC mutations are found in more than 80% of colorectal tumors. γ-Mangostin is a major bioactive compound present in Mangosteen (Garcinia mangostana) which possess significant anti-cancer activity. Herein, we investigated the effects of γ -Mangostin on colon cancer growth and elucidated its mechanistic action through Wnt signaling pathway.
Methods: HCT116, SW480 and RKO cell lines were used in the study. The effects of γ-Mangostin on cell proliferation were assessed by hexosaminidase and clonogenicity assays. Effects of γ-Mangostin on apoptosis were evaluated by cell cycle and western blot analysis. Moreover the effect of γ-Mangostin on colonosphere formation was also evaluated. Furthermore, the effect of γ-Mangostin on Wnt signaling proteins was evaluated by western blot analysis. The in vivo anti-cancer effect of γ -Mangostin was investigated on the HCT116 subcutaneous tumor xenograft model implanted in five-week-old male athymic nude mice. Further, the effect of γ -Mangostin was assessed by the specific marker expression in tissue samples by western blot analysis and immunohistochemistry.
Results: γ-Mangostin treatment resulted in a dose and time dependent inhibition of proliferation and colony formation in all the three cell lines. Treatment also induced colon cancer cells to undergo G0/G1 and S-phase arrest. Apoptosis was confirmed by increased levels of Bax/Bcl2 ratio, coupled with a reduction in cyclin D1. γ -Mangostin significantly reduced the number and size of colonospheres. Moreover, γ-Mangostin treatment decreased the expression of Wnt signaling proteins, which suggest that γ-Mangostin inhibits the colon cancer growth through Wnt signaling pathway. To determine the effect of γ-Mangostin on tumor growth in vivo, nude mice harboring HCT116 tumor xenografts in their flanks were administered with 5mg/Kg γ-Mangostin intraperitoneally for 21 days. γ-Mangostin treatment significantly reduced the tumor growth, with notably lower tumor volume and weight. Western blot and immunohistochemistry analyses revealed significant decrease in the expression of Wnt signaling proteins.
Conclusion: Together, these data suggest that γ-Mangostin inhibits colon cancer growth through Wnt signaling pathway. γ-Mangostin may be a potential therapeutic agent for colon cancer.
Citation Format: Balaji Krishnamachary, Dharmalingam Subramaniam, Thomas Attard, Seth Septer, Shrikant Anant. γ-Mangostin, a natural xanthone derivative targets Wnt signaling pathway in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5175. doi:10.1158/1538-7445.AM2017-5175