Polymethoxylated flavone sudachitin is a safe anticancer adjuvant that targets glycolysis in cancer‑associated fibroblasts

Chen,Shuhai; Nishi,Masaaki; Morine,Yuji; Yoshikawa,Kozo; Tokunaga,Takuya; Kashihara,Hideya; Takasu,Chie; Wada,Yuma; Yoshimoto,Toshiaki; Nakamoto,Akiko; Sakai,Tohru; Shimada,Mitsuo

doi:10.3892/ol.2022.13356

Polymethoxylated flavone sudachitin is a safe anticancer adjuvant that targets glycolysis in cancer‑associated fibroblasts

Authors:
- Shuhai Chen
- Masaaki Nishi
- Yuji Morine
- Kozo Yoshikawa
- Takuya Tokunaga
- Hideya Kashihara
- Chie Takasu
- Yuma Wada
- Toshiaki Yoshimoto
- Akiko Nakamoto
- Tohru Sakai
- Mitsuo Shimada
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Affiliations: Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Tokushima 770‑8503, Japan, Department of Public Health and Applied Nutrition, Institute of Biomedical Sciences, Tokushima University, Tokushima, Tokushima 770‑8503, Japan
Published online on: May 31, 2022 https://doi.org/10.3892/ol.2022.13356
Article Number: 236
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sudachitin is a polymethoxylated flavone found in the peel of Citrus sudachi, a unique specialty citrus fruit in Tokushima Prefecture, Japan. Previous reports have demonstrated that sudachitin has anti‑inflammatory and metabolic regulatory activities. However, to the best of our knowledge, no studies have explored whether sudachitin can act as an antitumor therapeutic agent by regulating metabolic functions in the tumor microenvironment. In the present study, cell proliferation and cytotoxicity assays were used to determine whether sudachitin inhibited the in vitro growth of liver cancer and pancreatic carcinoma, cholangiocarcinoma and colorectal cancer cells and to compare its toxicity against normal fibroblasts and induced cancer‑associated fibroblasts (CAFs). Using lactate assays and reverse transcription‑quantitative PCR, the effects of sudachitin on glycolysis in CAFs were investigated. The effects of CAFs on malignant tumor cells were evaluated in vitro using cell proliferation, wound healing and invasion assays. As result, sudachitin inhibited various types of tumor cells with different half‑maximal inhibitory concentrations. Treatment with 50 µM sudachitin for 48 h suppressed tumor and CAFs proliferation but was not cytotoxic against normal fibroblasts. This dose also inhibited glycolysis in CAFs and, thus, diminished their pro‑tumorigenic activities. Overall, the present study revealed that sudachitin has promise as a safe and widely available natural antitumor adjuvant.

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