Probiotic-derived ferrichrome induces DDIT3-mediated antitumor effects in esophageal cancer cells
Takehito Kunogi,
Hiroaki Konishi,
Aki Sakatani,
Kentaro Moriichi,
Chikage Yamamura,
Koji Yamamoto,
Shin Kashima,
Katsuyoshi Ando,
Nobuhiro Ueno,
Hiroki Tanaka,
Toshikatsu Okumura,
Mikihiro Fujiya
Affiliations
Takehito Kunogi
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Hiroaki Konishi
Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Aki Sakatani
Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Kentaro Moriichi
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Chikage Yamamura
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Koji Yamamoto
Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Shin Kashima
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Katsuyoshi Ando
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Nobuhiro Ueno
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Hiroki Tanaka
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Toshikatsu Okumura
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Mikihiro Fujiya
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan; Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Asahikawa, 078-8510, Japan; Corresponding author. Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan
Esophageal cancer, which is common among the elderly, has the poorest prognosis among gastrointestinal cancers. Previously, we demonstrated that ferrichrome, produced by the probiotic Lactobacillus casei, exhibited anti-tumor effects in various gastrointestinal cancers, including colorectal and gastric cancers, with minimal effects on non-cancerous intestinal cells. However, it remains unclear whether ferrichrome exerts anti-tumor effects in esophageal cancer. A sulforhodamine B assay revealed that ferrichrome suppressed esophageal adenocarcinoma (OE33, OE19) and squamous cell carcinoma (KYSE70) cells. Ki-67 staining indicated that ferrichrome inhibited the proliferation of esophageal cancer cells. Cell cycle analysis showed that ferrichrome inhibited the DNA synthesis. TUNEL staining revealed that ferrichrome-induced DNA fragmentation. We also confirmed the cleavage of caspase-9 and PARP in ferrichrome-treated cells. Reverse transcription polymerase chain reaction demonstrated an increase in the mRNA of DNA damage-inducible transcript 3 (DDIT-3), a key regulator of programmed cell death, in ferrichrome-treated OE33 cells. In an in vivo OE33 xenograft model, intraperitoneal administration of 5-mg/kg ferrichrome for 14 days resulted in an almost complete inhibition of tumor growth. However, 14 days of intraperitoneal administration of 20-mg/kg 5-fluorouracil (5-FU), but not 20-mg/kg ferrichrome, induced weight loss and myelosuppression in both young and aged mice. Our findings indicate that ferrichrome induces DNA damage-inducible transcript-3, thereby producing anti-tumor effects, including cell cycle arrest and apoptosis, with minimal adverse effects in esophageal cancer cells. This illustrates the high potential of ferrichrome as an anti-tumor drug against esophageal carcinoma.
