Rapamycins: Mechanisms of Action and Cellular Resistance

Huang, Shile; Bjornsti, Mary-Ann; Houghton, Peter J.

doi:10.4161/cbt.2.3.360

Cited by 289 publications

(233 citation statements)

References 105 publications

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“…4c; Table 3). Rapamycin is known to cause G1 arrest in differentiated cells (Huang et al 2003), and reduced S phase in the presence of rapamycin may account for reduced BrdU incorporation observed in vivo. Neither rapamycin nor metformin induced significant apoptosis (Fig.…”

Section: Neural Progenitor Proliferation In Vitro Is Reduced By Rapammentioning

confidence: 99%

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne

Goldberg

Parker

et al. 2013

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The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metforminmediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological AGE

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Section: Neural Progenitor Proliferation In Vitro Is Reduced By Rapammentioning

confidence: 99%

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne

Goldberg

Parker

et al. 2013

AGE

View full text Add to dashboard Cite

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“…Furthermore, the biological response (growth arrest versus apoptosis) of rapamycin is also known to depend on the oncogenic status of the cells, for example, rapamycin induces apoptosis in P53-deficient cells, whereas P53-proficient cells are resistant (Huang et al, 2003). This is particularly important for the efficacy of rapamycin treatment of sporadic cancers as it is well known that P53 is mutated in more than half of all human sporadic cancers.…”

Section: Synopsismentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…To test this possibility, we looked at whether p110g protein levels were affected by inhibition of mTOR by means other than 9AA treatment. Rapamycin is a specific chemical inhibitor of mTOR complex 1, which is involved in the regulation of translation (Huang et al, 2003). Treatment of HT1080 cells with rapamycin reduced p110g levels, indicating that p110g is translated through an mTOR-dependent mechanism ( Figure 3a).…”

Section: P110g Expression Is Decreased In Tumor Cells Treated With 9aamentioning

confidence: 99%

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

et al. 2009

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Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs. The small molecule 9-aminoacridine (9AA) and its derivative, the antimalaria drug quinacrine, have selective toxicity for tumor cells and can simultaneously suppress nuclear factor-jB (NF-jB) and activate p53 signaling. To investigate the mechanism underlying these drug activities, we used a combination of twodimensional protein separation by gel electrophoresis and mass spectrometry to identify proteins whose expression is altered in tumor cells by 9AA treatment. We found that 9AA treatment results in selective downregulation of a specific catalytic subunit of the phosphoinositide 3-kinase (PI3K) family, p110c. Further exploration of this observation demonstrated that the mechanism of action of 9AA involves inhibition of the prosurvival AKT/ mammalian target of rapamycin (mTOR) pathway that lies downstream of PI3K. p110c translation appears to be regulated by mTOR and feeds back to further modulate mTOR and AKT, thereby impacting the p53 and NF-jB pathways as well. These results reveal functional interplay among the PI3K/AKT/mTOR, p53 and NF-jB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by a single small molecule such as 9AA could result in efficacious and selective killing of transformed cells.

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Rapamycins: Mechanisms of Action and Cellular Resistance

Cited by 289 publications

References 105 publications

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

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