کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5823341 | 1118318 | 2014 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function
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کلمات کلیدی
ABCRho123Fumitremorgin CJAK2 inhibitorVerapamil (PubChem CID: 62969)VRPJanus Kinase 2TKIVCRABCC1JAK2FTCCSCsGAPDHSTAT3ABCG2MDRDOX3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide - 3- (4،5-dimethylthiazol-2-yl) -2،5-difenyltetrazolium bromideMTT - MTTP-glycoprotein - P-گلیکوپروتئینDoxorubicin - دوکسوروبیسینRhodamine 123 - رودامین 123cancer stem cell - سلولهای بنیادی سرطانیChemotherapeutic agents - عوامل شیمی درمانیsignal transducer and activator of transcription 3 - مبدل سیگنال و فعال کننده رونویسی 3Multidrug resistance - مقاومت چند داروییMultidrug resistance (MDR) - مقاومت چند دارویی (MDR)Tyrosine kinase inhibitor - مهار کننده تیروزین کینازVerapamil - وراپامیلVanadate - وناداتvincristine - وین کریستینMultidrug Resistance-associated Protein 1 - پروتئین مرتبط با مقاومت چند دارویی 1breast cancer resistance protein - پروتئین مقاومت به سرطان سینهATP-binding cassette - کیت اتصال به ATPglyceraldehyde-3-phosphate dehydrogenase - گلیسرالیدید-3-فسفات دهیدروژناز
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 91, Issue 2, 15 September 2014, Pages 144-156
Journal: Biochemical Pharmacology - Volume 91, Issue 2, 15 September 2014, Pages 144-156
نویسندگان
Shang-jun Tang, Li-kun Chen, Fang Wang, Yun-kai Zhang, Zhen-cong Huang, Kenneth Kin Wah To, Xiao-kun Wang, Tanaji T. Talele, Zhe-sheng Chen, Wei-qiang Chen, Li-wu Fu,