title: Dual-targeting hybrid peptide-conjugated doxorubicin for drug resistance reversal in breast cancer.
abstract: The extended use of doxorubicin (DOX) could be limited due to the emergence of drug resistance associated with its treatment. In addition to the overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), other mechanisms including apoptosis evasion and tumor cell survival may also be important contributor to drug resistance. Within this context, targeting extracellular signal-regulated kinases (ERK), one of the principle protein molecules in cell apoptosis has emerged as an attractive therapeutic concept. In this study, a dual-targeting hybrid peptide HAIYPRHGGCGMPKKKPTPIQLNP (T10-ERK), which is composed of ERK peptide inhibitor MPKKKPTPIQLNP, a thiol spacer (i.e., GGCG) and transferrin receptor (TfR)-binding peptide HAIYPRH, was designed. Then, this thiol-modified hybrid peptide was conjugated to DOXO-EMCH (6-maleimidocaproyl) hydrazone of DOX), forming a novel peptide-DOX conjugate T10-ERK-DOX. The structure and properties of this conjugate were characterized using (1)H NMR, mass spectrometry and HPLC. Using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of T10-ERK-DOX to reverse drug resistance was accessed as compared with free DOX and T10-DOX. As a result, T10-ERK-DOX demonstrated a much lower in vitro IC50 (20.8±1.1μM) and its in vivo extent of inhibition in mice was more evident (72.2±4.6%). Induction of various apoptosis pathways was also observed. Furthermore, the potency of ERK peptide inhibitor to reverse drug resistance was individually assessed, given the pronounced efficacy of T10-DOX indicated by our previous work. The results provided evidence of its additive effect with T10-DOX, which leads to greater efficacy and less susceptibility to drug resistance. Finally, the success of multi-targeting strategy in the present study implied that multi-target drugs with rational design could be more promising in cancer therapy.
authors: Nanjing Medical University, Nanjing, 211166, China.
authors: Yuan
authors: Y
authors: Sheng
authors: Nanjing Medical University, Nanjing, 211166, China.
authors: Yiwen
authors: Y
authors: You
authors: Nanjing Medical University, Nanjing, 211166, China. Electronic address: ychen@njmu.edu.cn.
authors: Yun
authors: Y
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010455:Peptides; C000620950:T10-ERK-DOX compound; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Doxorubicin; Drug resistance reversal; Dual-targeting hybrid peptide; ERK peptide inhibitor; Multi-target effect; TfR-binding peptide