Amoxicillin, a β-lactam antibiotic, enhances cisplatin sensitivity in cancer cells affecting mitochondria

Amoxicillin (AMPC) is a commonly used as an antibiotic. This study showed that AMPC enhanced the anticancer effect of cisplatin by inducing mitochondrial dysfunction. Compared with controls, treatment of cervical cancer (HeLa) and oral squamous cell carcinoma (SAS) cells with 10 μg/mL AMPC significantly increased mitochondrial reactive oxygen species levels, decreased mitochondrial membrane potential, and reduced mitochondrial Fe²⁺ levels. This concentration is equivalent to the maximum blood levels of AMPC used in Helicobacter pylori eradication. The viability of HeLa and SAS cells was significantly reduced when cisplatin was administrated after AMPC; however, this effect was not observed in normal human fibroblast-like lung cells (VA-13) or human periodontal ligament fibroblast (HPLF) cells. AMPC did not enhance the anticancer effect of docetaxel. The AMPC-enhanced anticancer effect of cisplatin was blocked by the iron-chelating agent phenanthroline, indicating that the effect was primarily driven by ferroptosis, an iron-dependent form of cell death. The expression levels of the AMPC transporters PEPT1 and PEPT2 were higher in cancer cells such as HeLa and SAS than in normal cells. This phenomenon facilitates greater AMPC uptake and mitochondrial dysfunction in cancer cells.