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

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.

The Impact of the Microbiome on Resistance to Cancer Treatment with Chemotherapeutic Agents and Immunotherapy

“…A combination treatment with gemcitabine together with Lactobacillus paracasei improved the efficacy of chemotherapy, showing lower levels of aspartate-aminotransferase (AST) and alanine aminotransferase (ALT) [ 181 ]. In addition, the antitumor effect of probiotic-derived ferrichrome ( Lactobacillus casei ) has been observed in 5-FU-resistant pancreatic cancer cells, presumably through p53 upregulation and induction of apoptosis [ 182 ]. Iwama et al reported that the effect of ferrichrome on CRC cells was superior to that of 5-FU or cisplatin [ 183 ].…”

“…Iwama et al reported that the effect of ferrichrome on CRC cells was superior to that of 5-FU or cisplatin [ 183 ]. These observations suggest that probiotics exhibit antitumor effects mediated by molecules such as ferrichrome and could therefore be used as antitumor drugs in the future [ 182 ].…”

Proteomics, Personalized Medicine and Cancer

“…This study suggests that ferrichrome can activate the JNK signaling pathway triggering apoptosis ( Figure 4 ), and is more effective with reduced adverse effects than the clinical drugs cisplatin and 5-fluorouracil. Further studies have found that ferrichrome can also restrain proliferation and induce apoptosis in other cancers, such as gastric cancer [ 199 ], HCC [ 200 ] and pancreatic cancer [ 201 ]. Fecal microbiota transplantation (FMT) is the reconstruction of the gut microbiota by transplanting fecal material from healthy donors to sick patients.…”

Microorganisms in chemotherapy for pancreatic cancer: An overview of current research and future directions

“…In addition, some components derived from probiotics also seem to exhibit antitumor activity. The ferrichrome extracted from Lactobacillus paracasei can inhibit the proliferation of pancreatic cancer cells and restrain pancreatic cancer cells resistant to 5-fluorouracil in a mouse model, indicating that the antitumor activity of probiotics may come from the active ingredients in probiotics [162]. In addition, probiotics seem to have the ability to reduce adverse postoperative reactions.…”