Abstract
FOLFOX (oxaliplatin, fluorouracil and calcium folinate) is the first-line chemotherapy regimen for colon cancer therapy in the clinic. It provides superior efficacy than oxaliplatin alone, but the underlying mechanism remains unclear. In the present study, pharmacomicrobiomics integrated with metabolomics was conducted to uncover the role of the gut microbiome behind this. First, in vivo study demonstrated that FOLFOX exhibited better efficacy than oxaliplatin alone in colon cancer animal models. Second, 16S rDNA gene sequencing analysis showed that the abundance of Akkermansia muciniphila (A. muciniphila) remarkably increased in the FOLFOX treated individuals and positively correlated with the therapeutic effect. Third, further exploration confirmed A. muciniphila colonization significantly enhanced the anti-cancer efficacy of FOLFOX. Last, metabolomics analysis suggested dipeptides containing branched-chain amino acid (BCAA) might be responsible for gut bacteria mediated FOLFOX efficacy. In conclusion, our study revealed the key role of A. muciniphila in mediating FOLFOX efficacy, and manipulating A. muciniphila might serve as a novel strategy for colon cancer therapy.
Highlights
Oxaliplatin is a diamine cyclohexane platinum derivative that shows better tolerance than cisplatin in terms of nephrotoxicity (Yuan et al, 2020)
Oxaliplatin is extensively applied for colon cancer therapy, it was often combined with other chemotherapeutics because of the severe adverse effects and poor prognosis (Kang et al, 2020)
Oxaliplatin treatment exhibited a less satisfied anti-cancer effect and decreased body weight compared with FOLFOX, which is consistent with previous reports (Panebianco et al, 2018; Heshiki et al, 2020)
Summary
Oxaliplatin is a diamine cyclohexane platinum derivative that shows better tolerance than cisplatin in terms of nephrotoxicity (Yuan et al, 2020). Oxaliplatin acts primarily through binding with inter- and intra-strand cross-links in DNA, forming DNA adducts, and thereby inhibiting cell DNA synthesis (Zimmermann et al, 2020). Oxaliplatin reached only ∼10% response rate when applied alone in clinical practice. Severe peripheral sensory neuropathy occurs in ∼10% of patients after six treatment cycles and the rate reaches ∼50% after nine cycles, which largely limited its further application (Cvitkovic and Bekradda, 1999; Zhang et al, 2020). Oxaliplatin is often applied in combination with fluorouracil (5-FU) and calcium folinate in the clinic (i.e., FOLFOX). Recent studies have suggested that gut microbiota, immune regulation, and tyrosine kinase Src might influence the anti-cancer effect of FOLFOX
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