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العنوان
Modulation of sunitinib Cytotxicity;Enphasis on cell Death/
الناشر
Amal kamal said Abdel-Azia Saad ElDin,
المؤلف
saad el din , amal kamal said abdel aziz
هيئة الاعداد
باحث / امل كمال سيد عبد العزيز
مشرف / اشرف عبد النعيم
مشرف / سامية شومان
مشرف / ابتهال الدمرداش
الموضوع
pharmacology and toxicology
تاريخ النشر
2014
عدد الصفحات
ix,277p.,
اللغة
الإنجليزية
الدرجة
الدكتوراه
التخصص
الصيدلة ، علم السموم والصيدلانيات (المتنوعة)
تاريخ الإجازة
1/1/2014
مكان الإجازة
جامعة عين شمس - كلية الصيدلة - ادوية وسموم
الفهرس
Only 14 pages are availabe for public view

from 304

from 304

Abstract

Abstract
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!!Sunitinib malate, a multityrosine kinase inhibitor, is currently used in the
treatment of imatinib-resistant gastrointestinal stromal tumor, renal cell
carcinoma and pancreatic neuroendocrine tumors. Although there are
ongoing clinical trials assessing its efficacy in other types of cancer,
increasing studies report emergence of sunitinib resistance. In the current
study, we aimed to explore the interplay between sunitinib cytotoxicity and
autophagy. Autophagy has dual roles in cancer; tumor cells utilize it to
survive under nutrient deprivation. Conversely, several anti-cancer agents
have been shown to trigger excessive autophagy that may contribute to
their cytotoxicity. Surprisingly, we found that sunitinib exhibited
“concentration-range” dependent effect on autophagy. Clinically-relevant
concentrations of sunitinib inhibited autophagy whereas higher ones
switched on the autophagic machinery. The present study also showed that
autophagic cell death is required for mediating sunitinib cytotoxicity. We
then explored whether sunitinib can modulate mTOR pathway and Bcl-2
family of proteins; both are crucial autophagy regulators that play prosurvival
roles in cancer. Strikingly, lower concentrations of sunitinib
increased Mcl-1 level and activated mTOR pathway. In contrast, higher
concentrations decreased Mcl-1 level. Ablation of Mcl-1 by RNAi
sensitized cancer cells to sunitinib. Outer–membrane but not matrix