title: An epirubicin-peptide conjugate with anticancer activity is dependent upon the expression level of the surface transferrin receptor.
abstract: Epirubicin (EPI) is one of the most widely used anticarcinogens; however, serious side effects, including cardiomyopathy and congestive heart failure, limit its long‑term administration. To overcome this problem, the HAIYPRH peptide ligand was used with EPI in the synthesis of a HAIYPRH‑EPI conjugate. The anticancer activity and cellular uptake of the conjugate were measured and evaluated. The results of the present study indicated that the cytotoxicity of HAIYPRH‑EPI was correlated with the expression of the cell surface transferrin receptor (TfR). The conjugate exerted high cytotoxicity and proapoptotic function when in an LN229 glioma cell line, which overexpresses surface TfR. It was hypothesized that transferrin (Tf) can promote cytotoxicity. Conversely, the conjugate exhibited very low cytotoxicity and proapoptotic function in a U87 glioma cell line, in which surface TfR expression was undetectable. In addition, fluorescence microscopy and flow cytometry methods were used to evaluate cellular uptake, and the results of these methods were consistent with the present hypotheses. The conjugate cellular uptake of the conjugate in LN229 cells was markedly higher compared with that in U87 cells, and it was hypothesized that Tf can enhance the uptake in LN229 cells. The cytotoxicity of HAIYPRH‑EPI was dependent upon the expression of surface TfR. Considering that the majority of cancer cells have high rates of iron uptake and surface TfR is generally overexpressed on cancer cells, it was speculated by the authors that HAIYPRH‑EPI may form part of an effective strategy for increasing the selectivity of EPI for cancer cells, as well as reducing its systemic toxicity. To confirm the hypothesis, the effects of HAIYPRH‑EPI on non‑cancerous cell lines were investigated. A future study will examine the side effects of HAIYPRH‑EPI, using a suitable delivery system in an animal model.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Jiadan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Thoracic Oncology, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Qiyu
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lou
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015251:Epirubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011990:Receptors, Transferrin / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C068126:CD71 antigen; D010455:Peptides; D011990:Receptors, Transferrin; D015251:Epirubicin