Ceftazidime and cefepime antagonize 5-fluorouracil’s effect in colon cancer cells

Abstract

Background Drug-drug interaction (DDI), which can occur at the pharmacokinetics and/or the pharmacodynamics (PD) levels, can increase or decrease the therapeutic or adverse response of a drug itself or a combination of drugs. Cancer patients often receive, along their antineoplastic agents, antibiotics such as ß-lactams to treat or prevent infection. Despite the narrow therapeutic indices of antibiotics and antineoplastic agents, data about their potential interaction are insufficient. 5-fluorouracil (5-FU), widely used against colon cancer, is known for its toxicity and large intra- and inter- individual variability. Therefore, knowledge about its interaction with antibiotics is crucial. Methods In this study, we evaluated at the PD levels, against HCT-116 colon cancer cells, DDI between 5-FU and several ß-lactams (ampicillin, benzypenicillin, piperacillin, meropenem, flucloxacillin, ceftazidime (CFT), and cefepime (CFP)), widely used in intensive care units. All drugs were tested at clinically achieved concentrations. MTT assay was used to measure the metabolic activity of the cells. Cell cycle profile and apoptosis induction were monitored, in HCT-116 and DLD-1 cells, using propidium iodide staining and Caspase-3/7 activity assay. The uptake of CFT and CFP by the cells was measured using LC-MS/MS method. Results Our data indicate that despite their limited uptake by the cells, CFT and CFP (two cephalosporins) antagonized significantly 5-FU-induced S-phase arrest (DLD-1 cells) and apoptosis induction (HCT-116 cells). Remarkably, while CFP did not affect the proliferation of colon cancer cells, CFT inhibited, at clinically relevant concentrations, the proliferation of DLD-1 cells via apoptosis induction, as evidenced by an increase in caspase 3/7 activation. Unexpectedly, 5-FU also antagonized CFT’s induced cell death in DLD-1 cells. Conclusion This study shows that CFP and CFT have adverse effects on 5-FU’s action while CFT is a potent anticancer agent that inhibits DLD-1 cells by inducing apoptotic cell death. Further studies are needed to decipher the mechanism(s) responsible for CFT’s effects against colon cancer as well as the observed antagonism between CFT, CFP, and 5-FU with the ultimate aim of translating the findings to the clinical settings.

Non-Steroidal Anti-Inflammatory Drug Effect on the Binding of Plasma Protein with Antibiotic Drug Ceftazidime: Spectroscopic and In Silico Investigation

“…It is also a beneficial drug in the case of certain wound infections and food poisoning. The anticancer activity of ceftazidime, in which it inhibits DLD-1 cells by inducing apoptotic cell death, was also reported very recently [15]. When ceftazidime given to the patients in the form of an injection given intravenously or intramuscularly, therefore, its interaction with HSA inside human body is highly anticipated.…”

Cefepime, a Cephalosporin, Induces the Apoptosis and Oxidative Stress in Nb2a Neuroblastoma Cells

“…Also according to cell cycle analysis as showing the percentage of cells in the different phases of the cell cycle (pre-G1, G0/G1, S, and G2/M) phases, it was detected that by affecting the cell cycle, cefepime slowed down the rate of cell division and caused the cells to arrest in the S and G2/M phases. Pfab et al (2022) showed that the cefepime alone increased slightly the cells in pre-G1 in HCT-116 cells up to 72 h post-treatment. The IC50 values and cytotoxic effects of pharmacological agents may change depending on the cell line used, the method of administration and the laboratory condition (Cortes et al, 2001).…”

Synthesis and antimicrobial testing of 5‐fluorouracil derivatives

“…Most importantly, drugs such as ceftazidime (CFT) and cefepime (CFP) have been shown to interfere with the action of 5‐FU. [ 19 ] As a result, it is critical to investigate 5‐FU derivatives to overcome the aforementioned issues.…”