Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies

Cheng, Fang; Zhang, Ruoqi; Sun, Chen; Ran, Qian; Zhang, Cuihan; Shen, Chen; Yao, Zhao; Wang, Miao; Song, Lin Lin; Peng, Cheng

doi:10.3389/fphar.2023.1231401

Cited by 7 publications

(2 citation statements)

References 188 publications

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“…Oxaliplatin, a potent neurotoxic chemotherapy used in CRC treatment, forms DNA-platinum adducts within cancer cells, disrupting DNA replication and cell division (17). While effective, it causes Oxaliplatin-induced peripheral neuropathy (OXAIPN), often requiring dose adjustments or interruptions due to its dose-limiting toxicity (18). The OXAIPN is reported to be a common side effect with both acute and chronic manifestations; also, approximately 80% of the CRC patients treated with either oxaliplatin alone or with other combinational chemotherapeutics experience neurotoxicity (19,20).…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Modekurty

2024

Preprint

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Background: Oxaliplatin is the standard treatment option for colorectal cancer (CRC) which is one of the most prevalent forms of cancer. However, patients suffer either treatment discontinuation or adverse post-treatment life quality due to Oxaliplatin-induced peripheral neuropathy. Methods: Our study has comprehensively explored the molecular mechanisms underlying Oxaliplatin-induced peripheral neuropathy via an extensive literature survey and identified multiple genes that may contribute to neuropathy and neurotoxicity. In addition to that, the publicly available bulk transcriptomic data of Illumina HiSeq 2500 platform, comprising the CRC tissue of 18 individuals' tumor and adjacent normal tissue was processed to identify differentially expressed genes (DEGs). Moreover, the single-cell RNA sequencing data of 10X genomics comprising normal and tumor tissues was subjected to analysis using Seurat and sctype R packages to uncover the cancer cells associated DEGs. Functional and pathway enrichment analysis was conducted using the Genecodis4 web-based tool. Next, RNA-seq data of CRC cell lines treated with Oxaliplatin compared with normal individuals, was also processed and DEGs were determined to validate the inhibition of a curated list of neuropathy-associated genes. Results: From literature and database searches, a total of 1367 genes, including ion channel genes, normal sensory neuron-associated genes, and axon-excitability-related genes were collected that are either reported to be or may be contributing to neuropathy among cancer survivors upon oxaliplatin administration. The bulk transcriptomic data analysis revealed 715 DEGs and single-cell analysis uncovered 2,854 DEGs. Identified upregulated genes from single-cell data analysis, such as LGALS4, SPINK4, TFF3, REG4, and REG1A were found to be associated with tumor proliferation via epithelial-mesenchymal transitions, oxidative stress, dysregulated immune system, and inflammation which can be utilized as potential targets to devise novel therapeutic strategies for CRC treatment. Furthermore, many proteins involved in axon-excitability (NGF, SOD1, ROBO1, CNTNAP2, CNTNAP2, and KCNMB1), normal sensory neuron (SOX10, APOE, SST, S1PR1, and KCND3), voltage-gated sodium (SCNN1B, SCNN1G, SCNN1A, SCN1B, and SCN2B), calcium (CACNA2D2, CACNA1A, CACNA1C, CACNA1E, and CACNA1F), and potassium channels (KCND3, KCNMB1, KCNMA1, KCNJ2, and KCNN4) showed downregulation due to the oxaliplatin administration in CRC cell lines and their inhibition may have led to neuropathy which needs further validations. Conclusion: Our study uncovers the downregulation of multiple genes upon oxaliplatin administration leading to neuropathy development and also elucidates potential therapeutic targets for better prognosis of CRC.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Modekurty

2024

Preprint

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“…Oxaliplatin cessation may result from a major dose-limiting clinical issue known as oxaliplatin-induced peripheral neurotoxicity. If treatment is discontinued, this neuropathy can be reversible [9]. As reported by the Food and Drug Administration (FDA), peripheral neuropathy affects more than 60% of oxaliplatin-treated patients [10].…”

Section: Introductionmentioning

confidence: 99%

Association of Genetic Polymorphism of ABCG2 Gene and the Occurrence of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer

Ahmed,

El Wakeel,

Saad

et al. 2023

Archives of Pharmaceutical Sciences Ain Shams University

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Oxaliplatin use in gastrointestinal malignancies is limited by neurotoxicity. This study aims to identify singlenucleotide polymorphisms (SNPs) in the ABCG2 gene associated with oxaliplatin-induced peripheral neuropathy (OIPN) in Egyptian Colorectal Cancer (CRC) patients treated with oxaliplatin-based chemotherapy (CT). All eligible CRC patients between the ages of 18 and 80 participated in the study, and those with a neurological illness or condition limiting neurologic function were excluded. On the first day of every CT cycle, OIPN was assessed and scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v.4. Blood was utilized to extract genomic DNA to detect SNPs in the ABCG2 gene (at rs2231137and at rs3114018) using High Resolution Melting (HRM) technique followed by direct sequencing method for every melting cluster using 3500 genetic analyzers for the samples selected from each cluster. The occurrence of grade 2-3 OIPN was higher in patients carrying the G/G genotype of ABCG2 (rs2231137) than those with the G/A genotype at the same locus (rs2231137) (96.7% versus 82.0%; P= 0.05). While, grade 2-3 OIPN occurrence was not significantly different in patients carrying genotypes (C/C, A/C, and A/A) of ABCG2 at rs3114018 (92.9%, 82.1% and 80.0% respectively; P= 0.309). In conclusion, the occurrence of OIPN among Egyptian Colorectal Cancer (CRC) patients was more associated with the G/G allele genotype of ABCG2 (rs2231137). While, patients carrying different genotypes (C/C, A/C, and A/A) of ABCG2 at rs3114018 were similarly associated with OIPN in this patient population.

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WTAP weakens oxaliplatin chemosensitivity of colorectal cancer by preventing PANoptosis

Tan,

Li,

Wang

et al. 2024

Cancer Letters

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Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies

Cited by 7 publications

References 188 publications

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Association of Genetic Polymorphism of ABCG2 Gene and the Occurrence of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer

WTAP weakens oxaliplatin chemosensitivity of colorectal cancer by preventing PANoptosis

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