Abstract 5475: DNA methylation regulator cordycepin suppresses gastric and colorectal cancer in combination with chemotherapy

Abstract Gastric cancer and colorectal cancer are the fifth and third most frequent malignant tumors, respectively. One of the most prevalent epigenetic characteristics in gastric and colorectal cancer is aberrant hypermethylation in the promoter of numerous tumor suppressor genes. Hypermethylation of the promoter inactivates tumor suppressor expression and contributes to tumor progression. DNA methyltransferases (DNMTs), which mediate DNA hypermethylation, are putative drug targets of cancer therapy. Several DNMTs inhibitors are under development. 5’-azacytidine and decitabine have been approved for the treatment of AML, myelodysplastic syndrome, and CMML. Clinical trials investigating DNMTs inhibitors in combination with other drugs are ongoing. However, clinical use of 5’-azacytidine and decitabine has been limited due to their toxicity. We have ever demonstrated that cordycepin, a major ingredient of Chinese traditional medicine Cordyceps, has activity of DNMTs inhibition. Treating cancer cells reversed hypermethylation of some tumor suppressor genes promoter, reactivated gene expression, and inhibited cancer cell proliferation. Here, we report the preclinical anti-cancer efficacy of Cordycepin in colorectal and gastric cancers in combination with chemotherapy drugs. In SGC-7901 human gastric cancer cells derived nude mice xenograft tumor model, mice were dosed 20mg/kg Cordycepin alone, 400mg/kg Capecitabine alone, or in combination orally, once daily, for 14 days. Tumor Growth Inhibition rate (TGI) of 89.2% was achieved in the combination therapy group comparing to 57.8% in the 400mg/kg Capecitabine mono-therapy group, and less than 10% in the Cordycepin alone group. Additionally, 20mg/kg Cordycepin plus 3mg/kg fluorouracil achieved TGI of 81.3% after 28 days of treatment in this model, comparing to 67.5% in the 6mg/kg fluorouracil monotherapy group. In HT-29 human colorectal cancer cells derived xenograft model, 20mg/kg Cordycepin plus 250mg/kg Capecitabine orally dosed once daily for 14 days showed TGI of 72.6%, similar to that treated by 400mg/kg Capecitabine alone (80.1%). 20mg/kg Cordycepin plus 2.5mg/kg Tegafur/Gimeracil/Oteracil once daily for 14 days had TGI of 76.7%, while 5mg/kg Tegafur/Gimeracil/Oteracil alone treatment group had TGI of 66.1%. 20mg/kg Cordycepin alone treatment showed only weak inhibition of tumor growth. Synergistic effects of Cordycepin and chemotherapy drugs were observed in treating both tested tumor models. Better tolerance was also shown in the combination therapy groups, as indicated by the mice body weight change. It is demonstrated that the DNMTs regulator Cordycepin has improved the anti-cancer activity and tolerance of chemotherapy drugs, such as Capecitabine, 5-FU, Tegafur/Gimeracil/Oteracil. Clinical development of Cordycepin and chemotherapy combination for cancer patients is strongly supported. Citation Format: Qing Dong, Yangze Cao, Jianyu Liu, Yang Qin. DNA methylation regulator cordycepin suppresses gastric and colorectal cancer in combination with chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5475.