التفاصيل البيبلوغرافية
| العنوان: |
The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression |
| المؤلفون: |
Harada, Masako, Benito, Juliana, Yamamoto, Shinichi, Kaur, Surinder, Arslan, Dirim, Ramirez, Santiago, Jacamo, Rodrigo, Platanias, Leonidas, Matsushita, Hiromichi, Fujimura, Tsutomu, Kazuno, Saiko, Kojima, Kensuke, Tabe, Yoko, Konopleva, Marina |
| بيانات النشر: |
Impact Journals LLC |
| سنة النشر: |
2015 |
| مصطلحات موضوعية: |
Research Paper, envir |
| الوصف: |
Mammalian target of rapamycin (mTOR) signaling is a critical pathway in the biology of acute myeloid leukemia (AML). Proviral integration site for moloney murine leukemia virus (PIM) serine/threonine kinase signaling takes part in various pathways exerting tumorigenic properties. We hypothesized that the combination of a PIM kinase inhibitor with an mTOR inhibitor might have complementary growth-inhibitory effects against AML. The simultaneous inhibition of the PIM kinase by pan-PIM inhibitor AZD1208 and of mTOR by selective mTORC1/2 dual inhibitor AZD2014 exerted anticancer properties in AML cell lines and in cells derived from primary AML samples with or without supportive stromal cell co-culture, leading to suppressed proliferation and increased apoptosis. The combination of AZD1208 and AZD2014 rapidly activated AMPKα, a negative regulator of translation machinery through mTORC1/2 signaling in AML cells; profoundly inhibited AKT and 4EBP1 activation; and suppressed polysome formation. Inhibition of both mTOR and PIM counteracted induction of heat-shock family proteins, uncovering the master negative regulation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. The novel combination of the dual mTOR inhibitor and pan-PIM inhibitor synergistically inhibited AML growth by effectively reducing protein synthesis through heat shock factor pathway suppression. |
| نوع الوثيقة: |
text |
| اللغة: |
English |
| العلاقة: |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741975Test/ |
| الإتاحة: |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741975Test/ |
| حقوق: |
undefined |
| رقم الانضمام: |
edsbas.2BC14C8F |
| قاعدة البيانات: |
BASE |
