mTOR Pathway and mTOR Inhibitors as Agents for Cancer Therapy

Baldo, Paolo; Cecco, Sara; Giacomin, Elisa; Lazzarini, Renzo; Rós, Barbara de Toledo; Marastoni, Stefano

doi:10.2174/156800908786733513

Cited by 96 publications

(83 citation statements)

References 140 publications

(145 reference statements)

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“…Angiogenesis is one of the key processes that mediates metastasis via HIF1a/VEGF signals and the Akt/mTOR signaling cascade (33). Several angiogenesis inhibitors are used clinically; however, Effect of SAD on the hypoxia-linked key angiogenesis protein and enzyme.…”

Section: Discussionmentioning

confidence: 99%

Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade

et al. 2015

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Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1a/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1a, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G 1 -S transitionphase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent. Cancer Res; 75(14); 2886-96. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade

et al. 2015

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“…Previous studies have shown that phase II and III trials have shown antitumor activity and survival advantage in patients with metastatic renal cancers treated with mTORI (Rao et al 2004;Baldo et al 2008;Amato et al 2009;Wang et al 2011). In the transplant population, the clinical effectiveness of mTORI for the prevention and treatment of renal cell carcinomas remained unclear.…”

Section: Management Of Cancer In Kidney Transplant Recipientsmentioning

confidence: 99%

Cancer in the Transplant Recipient

Chapman

Webster

Wong

2013

Cold Spring Harbor Perspectives in Medicine

230

187

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Malignancy has become one of the three major causes of death after transplantation in the past decade and is thus increasingly important in all organ transplant programs. Death from cardiovascular disease and infection are both decreasing in frequency from a combination of screening, prophylaxis, aggressive risk factor management, and interventional therapies. Cancer, on the other hand, is poorly and expensively screened for; risk factors are mostly elusive and/or hard to impact on except for the use of immunosuppression itself; and finally therapeutic approaches to the transplant recipient with cancer are often nihilistic. This article provides a review of each of the issues as they come to affect transplantation: cancer before wait-listing, cancer transmission from the donor, cancer after transplantation, outcomes of transplant recipients after a diagnosis of cancer, and the role of screening and therapy in reducing the impact of cancer in transplant recipients.

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“…However, the characteristic of poor water solubility of rapamycin limits its clinical application. For the water-soluble activity of drug mTOR after another, which for sirolimus (CC1779) has been approved for the clinical treatment of renal cell carcinoma, other similar drugs have also been approved for the reduction of renal transplant rejection and clinical treatment of coronary artery stenosis [35]. Another mTOR inhibitor-AZD8055, also spare the drug treatment of SLE [36], AZD8055 is an orally bio-agents, which can inhibit the activation of mTORC1 and mTORC2.…”

Section: Mtor Signaling Pathwaymentioning

confidence: 99%