Cephalosporin antibiotics specifically and selectively target nasopharyngeal carcinoma through HMOX1-induced ferroptosis.
AIMS
Many antibiotics derived from mold metabolites have been found to possess anticarcinogenic properties. We aimed to investigate whether they may elicit anticancer activity, especially against nasopharyngeal carcinoma.


MAIN METHODS
The response of nasopharyngeal and other carcinoma cell lines to cephalosporin antibiotics was evaluated in vitro and in vivo. MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cells. Flow cytometry was used to assess cell cycle parameters and apoptotic markers. Tumor growth was determined using a xenograft model in vivo. Microarray and RT-qPCR expression analyses investigate differential gene expression. Mechanistic assessment of HMOX1 in cefotaxime-mediated ferroptosis was tested with Protoporphyrin IX zinc.


KEY FINDINGS
Cephalosporin antibiotics showed highly specific and selective anticancer activity on nasopharyngeal carcinoma CNE2 cells both in vitro and vivo with minimal toxicity. Cefotaxime sodium significantly regulated 11 anticancer relevant genes in CNE2 cells in a concentration-dependent manner. Pathway analyses indicate apoptotic and the ErbB-MAPK-p53 signaling pathways are significantly enriched. HMOX1 represents the top one ranked upregulated gene by COS and overlaps with 16 of 42 enriched apoptotic signaling pathways. Inhibition of HMOX1 significantly reduced the anticancer efficacy of cefotaxime in CNE2 cells.


SIGNIFICANCE
Our discovery is the first to highlight the off-label potential of cephalosporin antibiotics as a specific and selective anticancer drug for nasopharyngeal carcinoma. We mechanistically show that induction of ferroptosis through HMOX1 induction mediates cefotaxime anticancer activity. Our findings provide an alternative treatment for nasopharyngeal carcinoma by showing that existing cephalosporin antibiotics are specific and selective anticancer drugs.
['He|Xiaoqiong|X|', 'Yao|Qian|Q|', 'Fan|Dan|D|', 'Duan|Ling|L|', 'You|Yutong|Y|', 'Liang|Wenjing|W|', 'Zhou|Zhangping|Z|', 'Teng|Song|S|', 'Liang|Zhuoxuan|Z|', 'Hall|Duane D|DD|', 'Song|Long-Sheng|LS|', 'Chen|Biyi|B|']
D000818:Animals D017209:Apoptosis D002453:Cell Cycle D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D002511:Cephalosporins D002681:China D000079403:Ferroptosis D051547:Heme Oxygenase-1 D006801:Humans D020935:MAP Kinase Signaling System D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D000077274:Nasopharyngeal Carcinoma D015398:Signal Transduction D023041:Xenograft Model Antitumor Assays
Cephalosporin antibiotics Nasopharyngeal carcinoma Ferroptosis Drug repositioning Heme oxygenase-1