Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

被引：471

作者：

Chappell, William H. ^{[1
]}

Steelman, Linda S. ^{[1
,2
]}

Long, Jacquelyn M. ^{[2
]}

Kempf, Ruth C. ^{[2
]}

Abrams, Stephen L. ^{[1
]}

Franklin, Richard A. ^{[1
]}

Baesecke, Joerg ^{[3
]}

Stivala, Franca ^{[4
]}

Donia, Marco ^{[4
]}

Fagone, Paolo ^{[4
]}

Malaponte, Graziella ^{[4
]}

Mazzarino, Maria C. ^{[4
]}

Nicoletti, Ferdinando ^{[4
]}

Libra, Massimo ^{[4
]}

Maksimovic-Ivanic, Danijela ^{[5
]}

Mijatovic, Sanja ^{[5
]}

Montalto, Giuseppe ^{[6
]}

Cervello, Melchiorre ^{[7
]}

Laidler, Piotr ^{[8
]}

Milella, Michele ^{[9
]}

Tafuri, Agostino ^{[10
]}

Bonati, Antonio ^{[11
]}

Evangelisti, Camilla ^{[12
]}

Cocco, Lucio ^{[12
]}

Martelli, Alberto M. ^{[12
,13
]}

McCubrey, James A. ^{[1
]}

机构：

[1] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC 27858 USA

[2] E Carolina Univ, Dept Phys, Greenville, NC 27858 USA

[3] Univ Gottingen, Dept Med, Gottingen, Germany

[4] Univ Catania, Dept Biomed Sci, Catania, Italy

[5] Univ Belgrade, Dept Immunol, Inst Biol Res Sinisa Stankovic, Belgrade, Serbia

[6] Univ Palermo, Dept Internal Med & Specialties, Palermo, Italy

[7] CNR, Ist Biomed & Immunol Mol Alberto Monroy, Palermo, Italy

[8] Jagiellonian Univ, Coll Med, Dept Med Biochem, Krakow, Poland

[9] Regina Elena Canc Ctr, I-00144 Rome, Italy

[10] Univ Roma La Sapienza, Dept Hematol Oncol, I-99161 Rome, Italy

[11] Univ Hosp Parma, Unit Hematol & Bone Marrow Transplantat, I-43100 Parma, Italy

[12] Univ Bologna, Dipartimento Sci Anat Umane & Fisiopatol Apparato, Bologna, Italy

[13] IOR, IGM CNR, Sez Bologna, Bologna, Italy

来源：

ONCOTARGET | 2011年 / 2卷 / 03期

关键词：

Targeted Therapy; Combination Therapy; Drug Resistance; Cancer Stem Cells; Aging; Senescence; Raf; Akt; PI3K; mTOR; CANCER STEM-CELLS; SIGNAL-REGULATED KINASE; PHOSPHATIDYLINOSITOL 3-KINASE/MAMMALIAN TARGET; BONE-MARROW MICROENVIRONMENT; SMALL-MOLECULE INHIBITORS; HUMAN OVARIAN-CANCER; PHOSPHOINOSITIDE 3-KINASE INHIBITION; ADVANCED HEPATOCELLULAR-CARCINOMA; CYCLIN-DEPENDENT KINASE; DNA-DAMAGE RESPONSE;

D O I：

10.18632/oncotarget.240

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

引用

页码：135 / 164

页数：30

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