کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10752832 | 1050332 | 2015 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The glucosylceramide synthase inhibitor PDMP sensitizes pancreatic cancer cells to MEK/ERK inhibitor AZD-6244
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کلمات کلیدی
PI3KS6K1PARPPDMPmTORFITCDMSO - DMSOMAPK - MAPKMTT - MTTChemo-sensitization - حساسیت شیمیایی شیمیاییDimethyl sulfoxide - دیمتیل سولفواکسیدceramide - سرامیدPancreatic cancer - سرطان پانکراسphosphatidylinositol-3-kinase - فسفاتیدیلینواستیل-3-کینازfluorescein isothiocyanate - فلوئورسین ایسوتیوسیاناتmammalian target of rapamycin - هدف پستانداران رپامایسینProtein phosphatase - پروتئین فسفاتازmitogen activated protein kinase - پروتئین کیناز فعال Mitogen فعال استpoly ADP ribose polymerase - پلی ADA ریبوز پلی مراز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Here we show that d,l-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a glycosphingolipid biosynthesis inhibitor, increases the sensitivity of pancreatic cancer cells to the novel MEK-ERK inhibitor AZD-6244. AZD-6244 and PDMP co-administration induced massive pancreatic cancer cell death and apoptosis, more potently than either drug alone. We discovered that AZD-6244 induced ceramide production in pancreatic cancer cells, yet the excess ceramide was metabolically removed in the long-term (24-48Â h). PDMP facilitated AZD-6244-induced ceramide production, and ceramide level remained elevated up to 48Â h. Meanwhile, exogenously-added cell-permeable short chain ceramide (C2) similarly sensitized AZD-6244's activity, the two caused substantial pancreatic cancer cell death and apoptosis. At the molecular level, PDMP and AZD-6244 co-treatment inactivated ERK1/2 and AKT-mTOR signalings simultaneously in pancreatic cancer cells, while either agent alone only affected one signaling. In summary, PDMP significantly increased the sensitivity of AZD-6244 in pancreatic cancer cells. This appears to involve a sustained ceramide production as well as concurrent block of ERK and AKT-mTOR signalings.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 456, Issue 3, 16 January 2015, Pages 821-826
Journal: Biochemical and Biophysical Research Communications - Volume 456, Issue 3, 16 January 2015, Pages 821-826
نویسندگان
Ting Wang, Jue Wei, Na Wang, Jia-Li Ma, Ping-Ping Hui,