Background: HMOX1 has a dual role in cancers, especially involving chemoresistance. We demonstrate that cephalosporin antibiotics exert strong anticancer activity in nasopharyngeal carcinoma mainly via drastic upregulation of HMOX1. background: HMOX1 has dual role in cancers, including involving in chemoresistance. We demonstrate that cephalosporin antibiotics exert specific and selective anticancer activity for nasopharyngeal carcinoma mainly via ferroptosis mediated by drastic upregulation of HMOX1. Infectious diseases are the most frequent and life-threatening complications in cancer patients. Cephalosporin antibiotics are the most current practice for treatment or prophylaxis of bacterial infectious diseases in cancer patients. Objectives: Cephalosporin antibiotics are commonly used for the treatment or prophylaxis of bacterial infectious diseases in cancer patients. It is unknown whether they lead to chemoresistance in cancer patients, especially in nasopharyngeal carcinoma patients, who are being treated or required prophylaxis for an infectious syndrome with cephalosporin antibiotics. Methods: MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cancer cells. Flow cytometry was used to detect apoptosis. Tumor growth was assessed using a xenograft model. Microarray and RT-qPCR expression analyses investigated differential gene expression. method: Cell viability assay and Clonogenic colony formation assay assessed the proliferation of cancer cells. Apoptosis was detected by flow cytometry. Tumor growth was assessed using a xenograft model. Microarray and RT-qPCR analyses investigated the regulated genes and signaling pathways. Results: Cefotaxime enhanced anticancer efficacy of cisplatin in nasopharyngeal carcinoma without enhancing the toxic side effects both in vitro and in vivo. However, cefotaxime significantly reduced the cytotoxicity of cisplatin in other cancer cell lines. Cefotaxime and cisplatin co-regulated 5 differential genes in CNE2 cells in a direction supporting the enhancement of anticancer efficacy, of which, THBS1 and LAPTM5 were further upregulated, STAG1, NCOA5, and PPP3CB were further downregulated. Out of the 18 apoptotic pathways significantly enriched in the combination group, THBS1 and HMOX1 overlapped in 14 and 12 pathways, respectively. Extrinsic apoptotic signaling pathway (GO: 2001236) was the only apoptotic pathway commonly enriched in cefotaxime group, cisplatin group and combination group, and THBS1 and HMOX1 were the overlapped genes of this pathway. THBS1 also overlapped in P53 signaling pathway and ECM-receptor interaction signaling pathway enriched by KEGG. result: Combination of cefotaxime and cisplatin specifically enhanced anticancer efficacy in nasopharyngeal carcinoma without enhancing the toxic side effects both in vitro and in vivo. However, cefotaxime significantly reduced the cytotoxicity of cisplatin in other cancer cell lines. Combination of cefotaxime and cisplatin co-regulated 5 differential genes in CNE2 cells in direction supporting the enhancement of anticancer efficacy, of which, THBS1 and LAPTM5 were further upregulated, STAG1, NCOA5, and PPP3CB were further downregulated. Overexpression of HMOX1 mediated by cefotaxime contributed to the specific and selective anticancer activity in nasopharyngeal carcinoma. Out of the 18 apoptotic pathways significantly enriched by the differential upgenes, THBS1 and HMOX1 overlapped in 14 and 12 pathways respectively. Extrinsic apoptotic signaling pathway (GO: 2001236) was the only significantly regulated apoptotic pathway commonly enriched in cefotaxime group, cisplatin group and combination group at the same time; and THBS1 and HMOX1 were the overlapped differential genes in this pathway. THBS1 was the overlapped gene in P53 signaling pathway and ECM-receptor interaction signaling pathway significantly enriched by KEGG. Conclusion: Cephalosporin antibiotics are chemosensitizers of conventional chemotherapeutic drugs in the chemotherapy of nasopharyngeal carcinoma, but they may lead to chemoresistance by cytoprotection in other cancers. Cefotaxime and cisplatin co-regulate THBS1, LAPTM5, STAG1, NCOA5 and PPP3CB suggesting their involvement in the enhancement of anticancer efficacy in nasopharyngeal carcinoma. Targeting of P53 signaling pathway and ECM-receptor interaction signaling pathway was correlated to the enhancement. With additional benefit for treatment or prophylaxis of an infectious syndrome, cephalosporin antibiotics can benefit the therapy of nasopharyngeal carcinoma either as anticancer agents or as chemosensitizers of chemotherapeutic drugs in combination chemotherapy. other: No
Background: Cephalosporin antibiotics can drastically upregulate the expression of HMOX1 in nasopharyngeal carcinoma cells. HMOX1 has dual role in cancer cells, and is involved in chemoresistance. Cephalosporin antibiotics are widely used in the treatment of bacteria infectious diseases in cancer patients. Whether they affect the efficacy of chemotherapy is unknown. Methods: Comparisons between cefotaxime and the combination of cefotaxime and cisplatin were carried out throughout the study. Cell viability was detected by MTT method. Influence on clone formation of cancer cells was investigated by plate clone formation assay. The in vivo anticancer effect was determined via cancer xenograft in mice. Flow cytometry analysis was used to detect the apoptosis. Microarray gene expression profiling was analyzed using Gene Ontology analysis, and the differential genes were validated by RT-qPCR. Results: Cefotaxime specifically, selectively and synergistically enhanced the anticancer efficacy of cisplatin in nasopharyngeal carcinoma both in vitro and in vivo without increasing the toxicity, but it inhibited the cytotoxic effects of cisplatin in other cancers. Combination of cefotaxime and cisplatin significantly regulated 5 genes in direction favoring the enhancement of anticancer efficacy; of which, THBS1 and LAPTM5 were upregulated; PPP3CB, STAG1 and NCOA5 were downregulated jointly. HMOX1 contributes to the anticancer efficacy in combination group. Upregulated genes significantly modulated 18 apoptotic pathways, downregulated genes mainly affected assembly of genetic materials. Conclusion: Cephalosporin antibiotics are excellent and safe sensitizers of conventional chemotherapy in the treatment of nasopharyngeal carcinoma, but should be carefully used in other cancers.
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