Updates of mTOR Inhibitors

Zhou, Hongyu; Luo, Yan; Huang, Shile

doi:10.2174/187152010793498663

Cited by 161 publications

(119 citation statements)

References 127 publications

(191 reference statements)

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“…To address this question, we used two modulators of autophagy known for their effects in the final steps in the process of autophagy: STF-62247 as an activator (Anbalagan et al, 2012) and chloroquine as an inhibitor (Long et al, 2013) of autophagy. We used rapamycin as an mTOR inhibitor (Zhou et al, 2010), and 3-MA as a PI3K class III inhibitor (O'Farrell et al, 2013), to modulate two proteins considered the major regulators of this process (Jung et al, 2010;O'Farrell et al, 2013). In stallion spermatozoa, STF-62247 and rapamycin induced a significant decrease in viability, whereas chloroquine and 3-MA had no effect on this parameter.…”

Section: Discussionmentioning

confidence: 99%

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The autophagy-related protein LC3 is processed in stallion spermatozoa during short-and long-term storage and the related stressful conditions

Aparicio

Muñoz

Salido

et al. 2016

Animal

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Use of cooled and frozen semen is becoming increasingly prevalent in the equine industry. However, these procedures cause harmful effects in the sperm cell resulting in reduced cell lifespan and fertility rates. Apoptosis and necrosis-related events are increased during semen cryopreservation. However, a third type of cell death, named autophagy, has not been studied during equine semen storage. Light chain (LC)3 protein is a key component of the autophagy pathway. Under autophagy activation, LC3-I is lipidated and converted to LC3-II. The ratio of LC3-II/LC3-I is widely used as a marker of autophagy activation. The main objective of this study was to investigate whether LC3 is processed during cooling, freezing and the stressful conditions associated with these technologies. A secondary objective was to determine if LC3 processing can be modulated and if that may improve the quality of cryopreserved semen. LC3 processing was studied by Western blot with a specific antibody that recognized both LC3-I and LC3-II. Viability was assessed by flow cytometry. Modulation of LC3-I to LC3-II was studied with known autophagy activators (STF-62247 and rapamycin) or inhibitors (chloroquine and 3-MA) used in somatic cells. The results showed that conversion of LC3-I to LC3-II increased significantly during cooling at 4°C, freezing/thawing and each of the stressful conditions tested (UV radiation, oxidative stress, osmotic stress and changes in temperature). STF-62247 and rapamycin increased the LC3-II/LC3-I ratio and decreased the viability of equine sperm, whereas chloroquine and 3-MA inhibited LC3 processing and maintained the percentage of viable cells after 2 h of incubation at 37°C. Finally, refrigeration at 4°C for 96 h and freezing at −196°C in the presence of chloroquine and 3-MA resulted in higher percentages of viable cells. In conclusion, results showed that an 'autophagy-like' mechanism may be involved in the regulation of sperm viability during equine semen cryopreservation. Modulation of autophagy during these reproductive technologies may result in an improvement of semen quality and therefore in higher fertility rates.Keywords: cryopreservation, refrigeration, viability, autophagy, sperm ImplicationsReproductive technologies with cooled and frozen semen have unquestionable advantages in animal breeding; however, semen preservation results in important injuries in the sperm cells, compromising their viability and hence the pregnancy rates. In the last decade, the scientific community has increased its efforts to improve current cryopreservation protocols. The results of the current study demonstrate that LC3, a protein involved in autophagy, is activated under stressful conditions during cryopreservation, and plays a role in regulating viability. Therefore, this study is of interest not only from a scientific point of view, but also for the improvement of semen quality, which could result in high fertility and finally increased economic gain.

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Section: Discussionmentioning

confidence: 99%

“…STF-62247 is a selective autophagy activator (Anbalagan et al, 2012). Rapamycin was used as an mTOR inhibitor (Zhou et al, 2010). 3-MA is an inhibitor of PI3K class III (O'Farrell et al, 2013).…”

Section: Incubation Mediamentioning

confidence: 99%

The autophagy-related protein LC3 is processed in stallion spermatozoa during short-and long-term storage and the related stressful conditions

Aparicio

Muñoz

Salido

et al. 2016

Animal

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“…RAD001 binds the intracellular protein FK-506-binding protein-12, forming a complex that inhibits the activity of mTORC1, thus affecting cell cycle progression, survival, angiogenesis and glycolysis. 17 RAD001 has been shown to be active against many subsets of leukemia, such as AML and acute promyelocytic leukemia, 18 non-Hodgkin's lymphoma 19 and other hematological malignancies, being under evaluation in several phase I/II clinical trials. 20 However, B-pre ALL was not included in these trials.…”

Section: Introductionmentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

et al. 2013

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B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/ mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G 0 /G 1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

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“…Another reason for the limited success is the presence of feedback loop between mTORC1 and AKT in certain tumor cells. It seems that mTORC1 inhibition by rapalogs fails to suppress a negative feedback loop that results in phosphorylation and activation of AKT [48,[53][54][55]. These limitations have led to the development of the second generation of mTOR inhibitors known as ATP-competitive mTOR kinase inhibitors [55].…”

Section: Clinical Indications Of M-tor I In Nontransplant Patients Anmentioning

confidence: 99%

m-TOR Inhibitors in the Current Practice

Alalawi¹,

Sharma²,

Halawa³

2017

J Clin Exp Nephrol

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Abstractfor long time, calcineurin-inhibitors (CNIs) was the best broadly used immunosuppressant in organ transplantation; since it had proven its efficacy in the reduction of acute rejection episodes and early graft loss, though their use in the long-term, are associated with chronic allograft nephropathy (CAN), besides it increases the cardiovascular risks such as diabetes, hypertension, and dyslipidemias. Moreover, CNIs in combination with other immunosuppressant's increases the risk of fatal infections and malignancy. Ultimately the introduction of the mammalian focus of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus in 1990s, had changed the face of transplantation and conveyed a great hope to transplant physicians as an innovative class of effective immunosuppressants with a unique mechanism and less nephrotoxic effects (1-6).In this review article we will try briefly to elicit the clinical indications, advantage and disadvantage of m-TOR inhibitors over other immunosuppressant's medications and their clinical indications inside and outside the transplant field.

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Updates of mTOR Inhibitors

Cited by 161 publications

References 127 publications

The autophagy-related protein LC3 is processed in stallion spermatozoa during short-and long-term storage and the related stressful conditions

The autophagy-related protein LC3 is processed in stallion spermatozoa during short-and long-term storage and the related stressful conditions

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

m-TOR Inhibitors in the Current Practice

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