XELOX in colorectal cancer: a convenient option for the future?

Lindsay, Colin R.; Cassidy, Jim

doi:10.1586/egh.10.90

Cited by 7 publications

(5 citation statements)

References 92 publications

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“…XELOX regimen (capecitabine plus oxaliplatin, 21 days per chemotherapy cycle) usually causes gastrointestinal toxicity in patients, such as a high diarrhea incidence. 35 To evaluate the effectiveness of mannose in alleviating chemotherapy-induced side effects, eight gastrointestinal cancer patients receiving XELOX regimen were recruited. Patients received conventional XELOX regimen (as a control cycle) suffered from severe diarrhea, and bowel movements (BMs) occurred 5–6 times per day in the first 5 days and even 3–4 times per day in the last 5 days of the chemotherapy cycle.…”

Section: Resultsmentioning

confidence: 99%

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P

Wang

Liu

et al. 2023

Cell Res

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Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

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Section: Resultsmentioning

confidence: 99%

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P

Wang

Liu

et al. 2023

Cell Res

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“…Xelox is widely used as a first-line chemotherapeutic regimen for primary CRC. However, the response is unsatisfactory due to the lack of effective predictive markers of sensitivity to treatment [35,36]. It has been shown that EMT plays an important role in the progression of drug sensitivity [37].…”

Section: Discussionmentioning

confidence: 99%

PPP2R1B abolishes colorectal cancer liver metastasis and sensitizes Oxaliplatin by inhibiting MAPK/ERK signaling pathway

Liu,

Tang,

Gao

et al. 2024

Cancer Cell Int

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Background Patients with colorectal cancer (CRC) with liver metastasis or drug resistance have a poor prognosis. Previous research has demonstrated that PPP2R1B inactivation results in the development of CRC. However, the role of PPP2R1B in CRC metastasis and drug resistance is unclear. Methods Venny 2.1 was used to determine the intersection between survival-related differentially expressed genes (DEGs) and liver metastasis-related DEGs according to RNA-seq data from The Cancer Genome Atlas (TCGA) and the GEO database (GSE179979). LC‒MS/MS and coimmunoprecipitation were performed to predict and verify the substrate protein of PPP2R1B. Gene Set Variation Analysis (GSVA) was subsequently utilized to assess pathway enrichment levels. The predictive performance of PPP2R1B was assessed by regression analysis, Kaplan–Meier (KM) survival analysis and drug sensitivity analysis. Immunohistochemistry (IHC), qRT-PCR and western blotting were performed to measure the expression levels of related mRNAs or proteins. Biological features were evaluated by wound healing, cell migration and invasion assays and CCK-8 assays. A mouse spleen infection liver metastasis model was generated to confirm the role of PPP2R1B in the progression of liver metastasis in vivo. Results According to bioinformatics analysis, PPP2R1B is significantly associated with liver metastasis and survival in CRC patients, and these findings were further verified via immunohistochemistry (IHC), qPCR and Western blotting. Pathway enrichment and LC‒MS/MS analysis revealed that PPP2R1B is negatively associated with the MAPK/ERK signalling pathway. Additionally, PD98059, a MAPK/ERK pathway inhibitor, inhibited EMT in vitro by reversing the changes in key proteins involved in EMT signalling (ZEB1, E-cadherin and Snail) and ERK/MAPK signalling (p-ERK) mediated by PPP2R1B. Oxaliplatin sensitivity prediction and validation revealed that PPP2R1B silencing decreased Oxaliplatin chemosensitivity, and these effects were reversed by PD98059 treatment. Moreover, PPP2R1B was coimmunoprecipitated with p-ERK in vitro. A negative correlation between PPP2R1B and p-ERK expression was also observed in clinical CRC samples, and the low PPP2R1B/high p-ERK coexpression pattern indicated a poor prognosis in CRC patients. In vivo, PPP2R1B silencing significantly promoted liver metastasis. Conclusions This study revealed that PPP2R1B induces dephosphorylation of the p-ERK protein, inhibits liver metastasis and increases Oxaliplatin sensitivity in CRC patients and could be a potential candidate for therapeutic application in CRC.

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“…FOLFOX/FLOX regimens, although effective, involve the intravenous administration of 5‐FU, whereas XELOX, a combination of oral capecitabine and intravenous oxaliplatin, constitutes a convenient and cost‐effective dosing for both patients and caregivers. Because of this, XELOX is gaining preference in palliative care and is currently the most commonly used combination in CRC …”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin/5-fluorouracil-based adjuvant chemotherapy as a standard of care for colon cancer in clinical practice: Outcomes of the ACCElox registry

Park

Zalcberg

et al. 2015

Asia-Pac J Clin Oncol

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XELOX in colorectal cancer: a convenient option for the future?

Cited by 7 publications

References 92 publications

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P

PPP2R1B abolishes colorectal cancer liver metastasis and sensitizes Oxaliplatin by inhibiting MAPK/ERK signaling pathway

Oxaliplatin/5-fluorouracil-based adjuvant chemotherapy as a standard of care for colon cancer in clinical practice: Outcomes of the ACCElox registry

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