Temsirolimus as a dual inhibitor of retinoblastoma and angiogenesis via targeting mTOR signalling

Chen, Zhe; Yang, Hongxia; Li, Zhi; Xia, Qinyun; Nie, Yao

doi:10.1016/j.bbrc.2019.06.127

Cited by 12 publications

(11 citation statements)

References 28 publications

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“…Gefitinib inhibits epidermal growth factor receptor (EGFR) [ 44 ], bosutinib is a tyrosine kinase inhibitor (TKI) [ 45 ], and axitinib inhibits the VEGF pathway [ 46 ]. Studies have also found a connection between the mTOR pathway and temsirolimus and metformin [ 47 , 48 ]. Metformin, an antidiabetic drug, can also be used to prevent cancer alone and in combination with other drugs, mainly by reducing glycemia to cut-off the PI3K/MAPK pathway, which is involved in cell growth, or by activating the AMPK pathway, targeting tumor metabolism angiogenesis, cancer stem cells, and other pathways [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

Che

et al. 2021

Oxidative Medicine and Cellular Longevity

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The mTOR pathway, a major signaling pathway, regulates cell growth and protein synthesis by activating itself in response to upstream signals. Overactivation of the mTOR pathway may affect the occurrence and development of cancer, but no specific treatment has been proposed for targeting the mTOR pathway. In this study, we explored the expression of mTOR pathway genes in a variety of cancers and the potential compounds that target the mTOR pathway and focused on an abnormal type of cancer, kidney renal clear cell carcinoma (KIRC). Based on the mRNA expression of the mTOR pathway gene, we divided KIRC patient samples into three clusters. We explored possible therapeutic targets of the mTOR pathway in KIRC. We predicted the IC50 of some classical targeted drugs to analyze their correlation with the mTOR pathway. Subsequently, we investigated the correlation of the mTOR pathway with histone modification and immune infiltration, as well as the response to anti-PD-1 and anti-CTLA-4 therapy. Finally, we used a LASSO regression analysis to construct a model to predict the survival of patients with KIRC. This study shows that mTOR scores can be used as tools to study various treatments targeting the mTOR pathway and that we can predict the recovery of KIRC patients through the expression of mTOR pathway genes. These research results can provide a reference for future research on KIRC patient treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

Che

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Sirolimus is a specific mTOR inhibitor and has wide effects on the mTOR signaling pathway, with potent antitumor action on various vascular malformations, including antiangiogenesis and antilymphangiogenesis, by reducing blood vessel or lymphatic vessel formation [22,23]. For example, Chen et al [24] reported that the mTOR inhibitor temsirolimus decreases proangiogenic cytokines and thereby tumor angiogenesis, most likely by inhibiting mTOR signaling. Rapamycin suppresses angiogenesis and lymphangiogenesis in melanomas by blocking the mTOR pathway and downregulating the expression of VEGF-A/VEGFR-2 and VEGF-C/VEGFR-3 [23].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Analysis of mTOR Pathway-Related Proteins in Kaposiform Hemangioendothelioma

Wang

Zheng

Sun³

et al. 2020

Dermatology

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Background: Mammalian target of rapamycin (mTOR) inhibitors have been shown to have excellent effects in the management of kaposiform hemangioendothelioma (KHE); however, the mechanism of action is unclear. This study identified the expressions of mTOR pathway-related proteins in different vascular tumors to provide insight into the pathogenesis of KHE. Methods: We retrospectively reviewed the pathologic specimens of 30 patients (KHE, 15; tufted angioma [TA], 5; infantile hemangioma [IH], 5; and lymphatic malformation [LM], 5). The immunohistochemical expression of mTOR-related proteins tuberous sclerosis complex 2 (TSC2), phosphatase and tensin homologue (PTEN), phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4EBP1), phosphorylated mTOR (p-mTOR), and phosphorylated ribosomal protein S6 kinase B1 (p-P70S6K) were analyzed using Image-Pro Plus software. KHE had the following pattern of expression in the spindle vascular endothelial cells: TSC2 (–); PTEN (–); p-4EBP1 (+); p-mTOR (+); and p-P70S6K (+). Results: All 3 patients treated with sirolimus had good responses. The TA results were similar to KHE with no significant differences (p-4EBP1: p = 0.0687; p-mTOR: p = 0.0832). The expressions of TSC2, PTEN, p-4EBP1, p-mTOR, and p-P70S6K were negative or weakly positive in IH with a statistically significant difference compared to KHE (p-4EBP1: p < 0.001; p-mTOR: p < 0.001; p-P70S6K: p < 0.001). LM had no significant differences when compared to KHE. Conclusions: The absence of TSC2 and PTEN caused abnormal activation of the mTOR signaling pathway and may be involved in the pathogenesis of KHE. The expression of mTOR-related proteins in TA and LM was similar to KHE, unlike IH. The KHE pattern of expression [PTEN (–), TSC2 (–), p-mTOR (+), p-P70S6K (+), and p-4EBP1 (+)] suggested that sirolimus may be a good therapeutic choice.

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“…Five human retinoblastoma cell lines, immortalized normal retinoblastoma pigmented epithelial cell line (RPE‐1), and normal human fibroblast BJ‐5ta were obtained from American Type Culture Collection or Chinese Academy of Sciences and were authenticated through short tandem repeat profiling analysis (Precision Biotechnology). Retinoblastoma and normal cells were maintained under the same culturing conditions as described in our previous studies 11,12 . Human primary retinal microvascular endothelial cell (HREC; Cell Systems) were cultured in basal M131 medium supplemented with microvascular growth supplement (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…Retinoblastoma and normal cells were maintained under the same culturing conditions as described in our previous studies. 11,12 Human primary retinal microvascular endothelial cell (HREC; Cell Systems) were cultured in basal M131 medium supplemented with microvascular growth supplement (Invitrogen). TAK-228 (Selleckchem, 99% purity with HPLC) and MHY1485 (Selleckchem, 99% purity with HPLC) were reconstituted in dimethyl sulfoxide (DMSO), sterilefiltered and stored in aliquots in −20°C.…”

Section: Cells Reagents Antibodies and Western Blotmentioning

confidence: 99%

mTOR inhibition by TAK‐228 is effective against growth, survival and angiogenesis in preclinical retinoblastoma models

Tang

Song

et al. 2022

Pharmacology Res & Perspec

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Mammalian target of rapamycin (mTOR) is a serine/threoninespecific kinase complex and its-mediated pathway play key roles in cell growth, proteo-synthesis, ribosomal biogenesis, transcriptional regulation, lipid metabolism, and autophagy. 1 The mTOR signalling pathway is the second most frequently altered pathway in human cancers and its aberrant activation contributes to tumor proliferation, angiogenesis, invasion and survival. 2 Angiogenesis, a formation of new blood vessel from pre-existing ones, is required for solid tumor development. 3 Retinoblastoma is characterized with extensive vascularization and thus targeting mTOR signalling might represent a more effective therapeutic strategy for retinoblastoma as mTOR is critically involved in both tumor and angiogenesis. In support of this hypothesis, we previously demonstrated that temsirolimus, FDA-approved mTOR-targeted drug for the treatment

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Temsirolimus as a dual inhibitor of retinoblastoma and angiogenesis via targeting mTOR signalling

Cited by 12 publications

References 28 publications

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

Immunohistochemical Analysis of mTOR Pathway-Related Proteins in Kaposiform Hemangioendothelioma

mTOR inhibition by TAK‐228 is effective against growth, survival and angiogenesis in preclinical retinoblastoma models

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