Probiotic‑derived ferrichrome inhibits the growth of refractory pancreatic cancer cells

Kita,Akemi; Fujiya,Mikihiro; Konishi,Hiroaki; Tanaka,Hiroki; Kashima,Shin; Iwama,Takuya; Ijiri,Masami; Murakami,Yuki; Takauji,Shuhei; Goto,Takuma; Sakatani,Aki; Ando,Katsuyoshi; Ueno,Nobuhiro; Ogawa,Naoki; Okumura,Toshikatsu

doi:10.3892/ijo.2020.5096

Probiotic‑derived ferrichrome inhibits the growth of refractory pancreatic cancer cells

Authors:
- Akemi Kita
- Mikihiro Fujiya
- Hiroaki Konishi
- Hiroki Tanaka
- Shin Kashima
- Takuya Iwama
- Masami Ijiri
- Yuki Murakami
- Shuhei Takauji
- Takuma Goto
- Aki Sakatani
- Katsuyoshi Ando
- Nobuhiro Ueno
- Naoki Ogawa
- Toshikatsu Okumura
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Affiliations: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078‑8510, Japan, Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Asahikawa 078‑8510, Japan, Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa 078‑8510, Japan, Asahikawa Medical University Hospital Emergency Unit, Asahikawa 078‑8510, Japan, Center for Advanced Research and Education, Department of Medicine, Asahikawa Medical University, Asahikawa 078‑8510, Japan
Published online on: July 8, 2020 https://doi.org/10.3892/ijo.2020.5096
Pages: 721-732
Copyright : © Kita et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Pancreatic cancer is associated with a poor prognosis due to challenges in early detection, severe progression of the primary tumor, metastatic lesions, and resistance to antitumor agents. However, previous studies have indicated a relationship between the microbiome and pancreatic cancer outcomes. Our previous study demonstrated that ferrichrome derived from Lactobacillus casei, a probiotic bacteria, exhibited tumor‑suppressive effects in colorectal and gastric cancer, and that the suppressive effects were stronger than conventional antitumor agents, such as 5‑fluorouracil (5‑FU) and cisplatin, suggesting that certain probiotics exert antitumorigenic effects. However, whether or not probiotic‑derived molecules, including ferrichrome, exert a tumor‑suppressive effect in other gastrointestinal tumors, such as pancreatic cancer, remains unclear. In the present study, it was demonstrated that probiotic‑derived ferrichrome inhibited the growth of pancreatic cancer cells, and its tumor‑suppressive effects were further revealed in 5‑FU‑resistant pancreatic cancer cells in vitro and in vivo in a mouse xenograft model. Ferrichrome inhibited the progression of cancer cells via dysregulation of the cell cycle by activating p53. DNA fragmentation and cleavage of poly (ADP‑ribose) polymerase were induced by ferrichrome treatment, suggesting that ferrichrome induced apoptosis in pancreatic cancer cells. A transcriptome analysis revealed that the expression p53‑associated mRNAs was significantly altered by ferrichrome treatment. Thus, the tumor‑suppressive effects of probiotics may mediated by probiotic‑derived molecules, such as ferrichrome, which may have applications as an antitumor drug, even in refractory and 5‑FU‑resistant pancreatic cancer.

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