کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2500767 1557307 2016 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Dual-targeting hybrid peptide-conjugated doxorubicin for drug resistance reversal in breast cancer
ترجمه فارسی عنوان
دوزوروبیسین هیپرتید هیپوتید دوگانه برای تغییر مقاومت دارو در سرطان پستان
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی علوم دارویی
چکیده انگلیسی

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 1H 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 ± 1.1 μM) 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.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: International Journal of Pharmaceutics - Volume 512, Issue 1, 15 October 2016, Pages 1–13
نویسندگان
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