Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis

El–Chemaly, Souheil; Taveira-DaSilva, Angelo M.; Goldberg, Hilary J.; Peters, Elizabeth; Haughey, Mary; Bienfang, Don C.; Jones, Amanda M.; Julien-Williams, Patricia; Cui, Ye; Villalba, Julian A.; Bagwe, Shefali; Maurer, Rie; Rosas, Iván O.; Moss, Joel; Henske, Elizabeth P.

doi:10.1016/j.chest.2017.01.033

Cited by 48 publications

(39 citation statements)

References 40 publications

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“…Whether rapamycin or rapamycin analogs have potential for improving healthspan and lifespan in humans is unclear, and their potential side effects are of significant concern. Rapamycin analogs that selectively target TORC1, which should have less side effects, have been proposed for treatment of diseases of aging (Arriola Apelo & Lamming, 2016;Bjedov et al, 2010;Chi et al, 2015;El-Chemaly et al, 2017;Miller et al, 2010).…”

Section: Proteostasismentioning

confidence: 99%

Measuring biological aging in humans: A quest

et al. 2019

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The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

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Section: Proteostasismentioning

confidence: 99%

Measuring biological aging in humans: A quest

et al. 2019

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“…Lacking effective single therapeutic drugs for LAM makes the combination drug regimens necessary, such as the rapamycin in combination with statins and autophagy inhibitors. Currently, sirolimus (rapamycin) and hydroxychloroquine (autophagy inhibitor) have reached the clinical phase I [13]. The mevalonate pathway metabolites are essential for cancer cell survival and growth.…”

Section: Discussionmentioning

confidence: 99%

“…The mTORC2 has been found to be insensitive to rapamycin, which could phosphorylate AKT at the Ser473 site and negatively regulate the AKT/PI3K pathway [12]. Rapamycin and rapalogs are the inhibitors of mTORC1, enhancing the rapid clinical transformation and benefiting many women with LAM [13,14]. However, some clinical studies have shown that the lung function would become deteriorated again and relapse would occur after the cessation of rapamycin for 24 months [15,16].…”

Section: Introductionmentioning

confidence: 99%

Zoledronic acid inhibits TSC2-null cell tumor growth via RhoA/YAP signaling pathway in mouse models of lymphangioleiomyomatosis

Zhao

et al. 2020

Cancer Cell Int

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Background: This study is to investigate the effects of zoledronic acid (ZA) on TSC2-null cell proliferation and on the tumor progression and recurrence in mouse models of lymphangioleiomyomatosis (LAM). Methods:Subcutaneous mouse models and LAM mouse models were established. Immunohistochemistry and immunofluorescence were performed to detect the protein expression levels. TUNEL assay was conducted to detect cell apoptosis. Immunoprecipitation was carried out to determine the interaction between proteins.Results: ZA prevented the growth of TSC2-null cells both in culture and in LAM mouse models. Compared with rapamycin, ZA more effectively promoted the apoptosis of TSC2-null cells. Moreover, combined with the rapamycin, ZA effectively suppressed the tumor recurrence after drug withdrawal and ZA inhibited the activity of GTPase RhoA by decreasing protein geranylgeranylation, resulting in changes of Yap nucleus translocation. Conclusion: ZA promotes cell apoptosis in TSC2-null cells through the RhoA/YAP signaling pathway. ZA may be used for the clinical treatment of LAM. Additional file 2: Fig. S1. ZA induces autophagy in TSC2-null cells. (A) Phosphorylated S6 and Yap expression detected by immunoblotting analysis in TSC2-null cells treated with ZA (25, 50, and 100 μM, respectively) for 24 h. (B) LC3 expression was detected by immunoblotting analysis in TSC2-null cells treated with ZA (25, 50, 75, and 100 μM, respectively) for 24 h. (C) Localization of LC3 and LAMP1 was analyzed by immunofluorescence in TSC2-null cells treated with ZA (25 and 50 μM, respectively) alone and RAPA (20 nM) for 24 h. (D) Localization of LC3 and LAMP1 was analyzed by immunofluorescence in TSC2-null cells treated with ZA (50 μM), RAPA (20 nM), and combination of ZA (50 μM) and GGPP (20 μM) for 24 h.The experiment was performed for three times. All data were presented as mean ± SEM. Compared with the placebo, * P < 0.05.

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“…Doxycycline, an inhibitor of MMP, was studied after a case report had suggested its efficacy in improving lung function [103], but no benefit was observed in one small randomized trial [104], and this treatment is not recommended [19]. Therapeutic strategies under investigation include autophagy inhibition by hydroxychloroquine [105] and reduction of estrogen synthesis by letrozole [106]. …”

Section: Lam and Tuberous Sclerosismentioning

confidence: 99%

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

Daccord¹,

Nicod²,

Lazor³

2017

Respiration

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Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or associated with tuberous sclerosis complex, and Birt-Hogg-Dubé syndrome. These disorders have similarities in their clinical expression, including occurrence in young adults, multiple pulmonary cysts, recurrent pneumothorax, skin hamartomas, and renal tumors. However, they markedly differ in their gender distribution, pathogenesis, disease course, and prognosis. Our knowledge on these two rare conditions is rapidly expanding. Management of lymphangioleiomyomatosis has substantially improved in the past decade with the understanding of its pathogenic mechanisms, the discovery of an effective therapy, and development of large cohorts and international guidelines. Birt-Hogg-Dubé syndrome has been described more recently and still awaits deeper understanding of its pathophysiology.

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Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis

Abstract: ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov.

Cited by 48 publications

References 40 publications

Measuring biological aging in humans: A quest

Measuring biological aging in humans: A quest

Zoledronic acid inhibits TSC2-null cell tumor growth via RhoA/YAP signaling pathway in mouse models of lymphangioleiomyomatosis

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

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