# Repurposing cephalosporins as excellent anticancer agents and chemosensitizers for inflammation-driven cancer therapy

## TL;DR

This study explores repurposing cephalosporin antibiotics as anticancer agents and chemosensitizers, particularly for inflammation-driven cancers like colorectal cancer.

## Contribution

The study identifies specific cephalosporins with dual anticancer and chemosensitizing effects and reveals HMOX1 as a central effector in these mechanisms.

## Key findings

- Cefamandole nafate and cefuroxime sodium show potent anti-colorectal cancer efficacy and chemosensitization.
- CUS synergistically enhances cisplatin and levofloxacin cytotoxicity through apoptosis and cell cycle arrest.
- CUS significantly up-regulates HMOX1, a key regulator of ferroptosis, in a dose-dependent manner.

## Abstract

Could cephalosporin antibiotics, extending beyond their established antimicrobial role, be repurposed as precision anticancer agents and chemosensitizers, particularly against inflammation-driven carcinogenesis? To address this question, this study systematically evaluated the anti-colorectal cancer efficacy of cephalosporins both as monotherapies and in synergistic combinations, elucidating their underlying molecular mechanisms. Employing combinatorial phenotypic screening (viability, cell cycle, apoptosis, colony formation), BALB/c nude mouse xenografts, and omics profiling (RNA-seq, RT-qPCR), we identified conserved anticancer pathways and core regulatory axes. Among 18 evaluated cephalosporins, therapeutic specificity was largely associated exclusively variable side-chain moieties, not the conserved β-lactam core. Cefamandole nafate (CAN) and cefuroxime sodium (CUS) demonstrated potent dual efficacy against colorectal cancer model while enhancing cisplatin chemosensitivity. Building on links to inflammation-driven chemosensitization, CUS synergistically potentiated cisplatin and levofloxacin cytotoxicity in colorectal cancer. This synergy was mechanistically driven by apoptosis induction, cell cycle arrest, significant up-regulation of HMOX1 (80-fold peak in combinations; 40-fold as monotherapy) and DDIT3, coupled with down-regulation of MUC1, CASC19, KRT23, SPNS3, LFNG, HS3ST1, NCOA5, and GJB4. Crucially, we reveal for the first time that CUS significantly up-regulates HMOX1 expression in HCT116 cells in a dose-dependent manner, establishing this ferroptosis regulator as the central effector governing both intrinsic anticancer activity and chemosensitization. This study unveils the translational potential of repurposing cephalosporins for combinatorial precision oncology strategies targeting inflammation-driven cancers.

The online version contains supplementary material available at 10.1038/s41598-025-25287-8.