Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency

Donehower, Lawrence A.

doi:10.18632/aging.100494

Cited by 25 publications

(11 citation statements)

References 8 publications

(15 reference statements)

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“…In our study, the older subjects (average age 74.5 years) remain healthy into old age, suggesting that the TLR1-mediated reduction in PMN function reported here, one of multiple deficiencies noted in immunosenescence [1], may be relevant to surviving other health complications, such as cancer or autoimmune diseases. Recent theories of aging and evidence that caloric restriction enhances longevity suggest paradoxically that reduction in anabolic processes may be beneficial to survival [38]. Caloric restriction is mediated in part by the TOR (target of rapamycin) pathway -- itself under the control of the circadian clock [39]— and while rapamycin inhibition of TOR signaling may be beneficial for longevity, during acute infection it can lead to inappropriate immune responses and increased tissue destruction [40].…”

Section: Discussionmentioning

confidence: 99%

Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging

Qian

Guo²,

Wang³

et al. 2014

Aging

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Section: Discussionmentioning

confidence: 99%

Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging

Qian

Guo²,

Wang³

et al. 2014

Aging

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“…[41-43]The mechanism of acquired resistance to rapamycin analogs remains unknown at this time. There is increasing recognition that tumors evolve with progression and with treatment pressure.…”

Section: Discussionmentioning

confidence: 99%

Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors

et al. 2014

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We tested the antitumor efficacy of mTOR catalytic site inhibitor MLN0128 in models with intrinsic or acquired rapamycin-resistance. Cell lines that were intrinsically rapamycin-resistant as well as those that were intrinsically rapamycinsensitive were sensitive to MLN0128 in vitro. MLN0128 inhibited both mTORC1 and mTORC2 signaling, with more robust inhibition of downstream 4E-BP1 phosphorylation and cap-dependent translation compared to rapamycin in vitro. Rapamycin-sensitive BT474 cell line acquired rapamycin resistance (BT474 RR) with prolonged rapamycin treatment in vitro. This cell line acquired an mTOR mutation (S2035F) in the FKBP12-rapamycin binding domain; mTORC1 signaling was not inhibited by rapalogs but was inhibited by MLN0128. In BT474 RR cells, MLN0128 had significantly higher growth inhibition compared to rapamycin in vitro and in vivo. Our results demonstrate that MLN0128 may be effective in tumors with intrinsic as well as acquired rapalog resistance. mTOR mutations are a mechanism of acquired resistance in vitro; the clinical relevance of this observation needs to be further evaluated.

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“…Inhibitors of mTOR can suppress geroconversion, protecting adult stem cells from undergoing premature cell senescence while simultaneously preventing their oncogenic transformation [35]. Amongst mTOR inhibitors, Rapamycin has been defined as a “longevity enhancer and cancer preventative agent” in the context of p53 deficiency [36]. Indeed, continuous treatment with Rapamycin or a novel Rapamycin formulation (Rapatar) delayed carcinogenesis in tumor-prone p53 + / − and p53 − / − mice respectively, most likely by slowing down the process of aging [37, 38].…”

Section: Introductionmentioning

confidence: 99%

mTOR pathway in colorectal cancer: an update

2013

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The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development, particularly due to the fact that it plays such a crucial role in cancer biology. In addition, next-generation mTOR inhibitors have become available, marking an exciting new phase in mTOR-based therapy. However, the verdict on their therapeutic efectiveness remains unclear. Here we review phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling as one of the primary mechanisms for sustaining tumor outgrowth and metastasis, recent advances in the development of mTOR inhibitors, and current studies addressing mTOR activation/inhibition in colorectal cancer (CRC). We will also discuss our recent comparative study of diferent mTOR inhibitors in a population of colon cancer stem cells (CSCs), and current major challenges for achieving individualized drug therapy using kinase inhibitors.

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Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency

Cited by 25 publications

References 8 publications

Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging

Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging

Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors

mTOR pathway in colorectal cancer: an update

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