J Cancer 2022; 13(8):2607-2619. doi:10.7150/jca.65506 This issue

Research Paper

3,3'-Diindolylmethane plus Eflornithine suppress DNA Replication and Cell Cycle in Esophageal Squamous Cell Carcinoma in vivo

Fayang Ma1,2*, Fangfang Liu1,2*, Wenna Nie2, Kyle Laster2, Xueli Tian1,2, Bingbing Lu1,2, Zushi Geng3, Ruihua Bai4, Dong Joon Kim1,2, Kangdong Liu1,2✉, Zigang Dong1,2✉

1. Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450008, China.
2. China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.
3. Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
4. The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.
*These authors contributed equally to this work.

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Citation:
Ma F, Liu F, Nie W, Laster K, Tian X, Lu B, Geng Z, Bai R, Kim DJ, Liu K, Dong Z. 3,3'-Diindolylmethane plus Eflornithine suppress DNA Replication and Cell Cycle in Esophageal Squamous Cell Carcinoma in vivo. J Cancer 2022; 13(8):2607-2619. doi:10.7150/jca.65506. Available from https://www.jcancer.org/v13p2607.htm

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Abstract

Graphic abstract

Esophageal squamous cell carcinoma (ESCC) is a malignant cancer that is responsible for a high mortality rate; it accounts for approximately 90% of the 456,000 esophageal cancer (EC) cases diagnosed annually. Effective natural or synthesized compounds to prevent, treat, and/or inhibit ESCC relapse are desperately needed. The natural di-indole compound 3,3'-diindolylmethane (DIM) is abundant in cruciferous vegetables and shows potent anti-tumor effects in multiple cancers. The synthesized Eflornithine (DFMO) is clinically used to treat African sleeping sickness. We demonstrated that the combination of DIM+DFMO could significantly suppress the ESCC growth in the in vivo study of three patient-derived xenograft (PDX) cases. Then, the corresponding underlying anticancer mechanisms were investigated via the isobaric tags for relative and absolute quantification (iTRAQ) on the proteome level. We found that the DNA Replication and Cell Cycle were the top-2 most significantly downregulated signaling pathways following the DIM+DFMO treatment. Correspondingly and interestingly, these two pathways were the top-2 upregulated ones in clinic ESCC tumors. Moreover, the involved differentially expressed genes (DEGs) including MCM2, MCM3, MCM5, MCM6, MCM7, CDK1, and LIG1 were all inversely downregulated by DIM+DFMO treatment. In the limited clinical study in two ESCC cases, the administration of DIM (250mg) +DFMO (500 mg) once daily showed favorable results, including alleviated swallowing difficulties, decreased blood tumor markers (CA19-9, CA15-3 and AFP), and no severe toxicity in at least one month progression free survival period. We concluded that DIM+DFMO is a promising therapeutic combination for ESCC treatment via the suppression of DNA Replication and Cell Cycle activities. However, these therapeutic effects should be verified in large cohort clinical trials with sufficient cases.

Keywords: Esophageal squamous cell carcinoma, 3, 3'-diindolylmethane, eflornithine, proteomics