scholarly journals Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents

2008 ◽  
Vol 183 (1) ◽  
pp. 101-116 ◽  
Author(s):  
Michael Degtyarev ◽  
Ann De Mazière ◽  
Christine Orr ◽  
Jie Lin ◽  
Brian B. Lee ◽  
...  

Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue–null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal autophagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H+–adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PI3K–Akt pathway inhibition.

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e113250 ◽  
Author(s):  
Pamela Ovadje ◽  
Dennis Ma ◽  
Phillip Tremblay ◽  
Alessia Roma ◽  
Matthew Steckle ◽  
...  

2021 ◽  
Vol 22 (16) ◽  
pp. 8372
Author(s):  
Ana María Zárate ◽  
Christian Espinosa-Bustos ◽  
Simón Guerrero ◽  
Angélica Fierro ◽  
Felipe Oyarzún-Ampuero ◽  
...  

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.


2019 ◽  
Vol 71 (1) ◽  
pp. 165-180 ◽  
Author(s):  
Tomasz Kowalczyk ◽  
Przemysław Sitarek ◽  
Ewa Skała ◽  
Monika Toma ◽  
Marzena Wielanek ◽  
...  

Endocrinology ◽  
2019 ◽  
Vol 160 (7) ◽  
pp. 1600-1612 ◽  
Author(s):  
Andrew V Schally ◽  
Xianyang Zhang ◽  
Renzhi Cai ◽  
Joshua M Hare ◽  
Riccarda Granata ◽  
...  

Abstract In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use.


PLoS ONE ◽  
2010 ◽  
Vol 5 (8) ◽  
pp. e12176 ◽  
Author(s):  
Dan-Dan Li ◽  
Jing-Feng Guo ◽  
Jia-Jia Huang ◽  
Lin-Lin Wang ◽  
Rong Deng ◽  
...  

2009 ◽  
Vol 8 (1) ◽  
pp. 11 ◽  
Author(s):  
Keqiang Zhang ◽  
Shuya Hu ◽  
Jun Wu ◽  
Linling Chen ◽  
Jianming Lu ◽  
...  

2014 ◽  
Vol 110 ◽  
pp. S104
Author(s):  
D. Viertl ◽  
A. Annibaldi ◽  
O. Matzinger ◽  
M.-C. Vozenin ◽  
C. Widmann ◽  
...  

2018 ◽  
Vol 9 ◽  
Author(s):  
Yi-Wen Wu ◽  
Kai-Cheng Hsu ◽  
Hsueh-Yun Lee ◽  
Tsui-Chin Huang ◽  
Tony E. Lin ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document