Rapamycin inhibits the growth of glioblastoma (original) (raw)
Related papers
2011
Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 mg/ mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All doseescalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.
Pharmaceuticals
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median duration of survival of approximately 14 months after diagnosis. High resistance to chemotherapy remains a major problem. Previously, BTK has been shown to be involved in the intracellular signal transduction including Akt/mTOR signaling and be critical for tumorigenesis. Thus, we aim to evaluate the effect of BTK and mTOR inhibition in GBM. We evaluated the viability of GBM cell lines after treatment with acalabrutinib and/or rapamycin through a SRB staining assay. We then evaluated the effect of both drugs on GBM stem cell-like phenotypes through various in vitro assay. Furthermore, we incubated HUVEC cells with tumorsphere conditioned media and observed their angiogenesis potential, with or without treatment. Finally, we conducted an in vivo study to confirm our in vitro findings and analyzed the effect of this combination on xenograft mice models. Drug combination assay demonstrated a sy...
Cancer research, 2001
We examined the cytotoxicity of the immunosuppressant agent rapamycin and its analogue CCI-779 in human brain tumor cell lines in vitro and in vivo as single agents and in combination with standard chemotherapeutic drugs. In the rapamycin-sensitive PNET/MB cell line DAOY, rapamycin exhibited additive cytotoxicity with cisplatin and with camptothecin. In vivo, CCI-779 delayed DAOY xenograft growth by 160% after 1 week and 240% after 2 weeks of systemic treatment, compared with controls. Single high-dose treatment induced 37% regression of tumor solume. Growth inhibition of DAOY xenografts was 1.3 times greater after simultaneous treatment with CCI-779 and cisplatin than after cisplatin alone. Interestingly, CCI-779 also produced growth inhibition of xenografts derived from U251 malignant glioma cells, a human cell line resistant to rapamycin in vitro. These studies suggest that the rapamycin analogue CCI-779 is an important new agent to investigate in the treatment of human brain tum...
Molecular Cancer Therapeutics, 2011
The identification of mammalian target of rapamycin (mTOR) as a major mediator of neurofibromatosis-1 (NF1) tumor growth has led to the initiation of clinical trials using rapamycin analogs. Previous studies from our laboratory have shown that durable responses to rapamycin treatment in a genetically engineered mouse model of Nf1 optic glioma require 20 mg/kg/day, whereas only transient tumor growth suppression was observed with 5 mg/kg/day rapamycin despite complete silencing of ribosomal S6 activity. To gain clinically relevant insights into the mechanism underlying this dose-dependent effect, we used Nf1-deficient glial cells in vitro and in vivo. First, there was an exponential relationship between blood and brain rapamycin levels. Second, we show that currently used biomarkers of mTOR pathway inhibition (phospho-S6, phospho-4EBP1, phospho-STAT3, and Jagged-1 levels) and tumor proliferation (Ki67) do not accurately reflect mTOR target inhibition or Nf1-deficient glial growth sup...
Mammalian target of rapamycin: master regulator of cell growth in the nervous system
Histology and histopathology, 2007
The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our curre...
Neurochemical Research, 2010
Glioblastoma Multiforme (GBM) is a malignant primary brain tumor associated with poor survival rate. PI3K/Akt pathway is highly upregulated in gliomas due to deletion or mutation of PTEN and its activation is associated with tumor grade. mTOR is downstream from PI3K/Akt pathway and it initiates translation through its action on S6K and 4E-BP1. mTOR is an important therapeutic target in many cancers, including glioblastomas. Rapamycin and its analogues are known to inhibit mTOR pathway; however, they also show simultaneous upregulation of Akt and eIF4E survival pathways on inhibition of mTOR, rendering cells more resistant to rapamycin treatment. In this study we investigated the effect of combination treatment of rapamycin with isoflavones such as genistein and biochanin A on mTOR pathway and activation of Akt and eIF4E in human glioblastoma (U87) cells. Our results show that combination treatment of rapamycin with isoflavones, especially biochanin A at 50 μM, decreased the phosphorylation of Akt and eIF4E proteins and rendered U87 cells more sensitive to rapamycin treatment when compared to cells treated with rapamycin alone. These results suggest the importance of combining chemopreventive with chemotherapeutic agents in order to increase the efficacy of chemotherapeutic drugs.
Rapamycin pre-treatment protects against apoptosis
Human Molecular Genetics, 2006
Macroautophagy (generally referred to as autophagy) mediates the bulk degradation of cytoplasmic contents, including proteins and organelles, in lysosomes. Rapamycin, a lipophilic, macrolide antibiotic, induces autophagy by inactivating the protein mammalian target of rapamycin (mTOR). We previously showed that rapamycin protects against mutant huntingtin-induced neurodegeneration in cell, fly and mouse models of Huntington's disease [Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 1107-1117, Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J. et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 585-595]. This protective effect of rapamycin was attributed to enhanced clearance of the mutant protein via autophagy [Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 1107-1117, Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J. et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 585-595]. Here, we show that rapamycin may have additional cytoprotective effects--it protects cells against a range of subsequent pro-apoptotic insults and reduces paraquat toxicity in Drosophila. This protection can be accounted for by enhanced clearance of mitochondria by autophagy, thereby reducing cytosolic cytochrome c release and downstream caspase activation after pro-apoptotic insults. Thus, rapamycin (pro-autophagic) treatment may be useful in certain disease conditions (including various neurodegenerative diseases) where a slow but increased rate of apoptosis is evident, even if they are not associated with overt aggregate formation.
Magnetic Resonance in Medicine, 2019
Purpose: The mammalian target of rapamycine (mTOR) is an enzyme that regulates cell metabolism and proliferation. It is up-regulated in aggressive tumors such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose Chemical Exchange Saturation Transfer (glucoCEST) signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment and hence glucoCEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment. Methods: A human U87-EGFRvIII xenograft model in mice was studied. The mice were treated with an mTOR inhibitor, rapamycin. The effect of the treatment was evaluated in vivo with dynamic glucoCEST MRI. Results: Rapamycin treatment led to significant increases (P < 0.001) in dynamic glucose enhanced (DGE) signal in both the tumor and contralateral brain as compared to the no-treatment group, namely a maximum enhancement of 3.7%±2.3% (tumor, treatment) versus 1.9%±0.4% (tumor, no-treatment), 1.7%±1.1% (contralateral, treatment), and 1.0%±0.4% (contralateral, no treatment). DGE-contrast remained consistently higher in treatment versus no-treatment groups for the duration of the experiment (17min). This was confirmed with area-under-curve analysis.
Clinical Cancer Research, 2007
Vinblastine and rapamycin displayed synergistic inhibition of human neuroblastomarelated angiogenesis. Here, we studied the antitumor activity of vinblastine and rapamycin against human neuroblastoma. Experimental Design: Cell proliferation, cell cycle progression, and apoptosis were evaluated by measuring 3 H-thymidine incorporation, bromodeoxyuridine uptake, and phosphatidylserine exposure, respectively. The in vivo sensitivity of neuroblastoma cells to vinblastine and rapamycin was determined in orthotopic neuroblastoma-engrafted mice. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. Results: Each compound alone was able to induce a dose-dependent significant inhibition of cell proliferation, with a dramatically enhanced antiproliferative effect for the drugs used in combination. A marked G 2-M cell cycle arrest with a nearly complete depletion of S phase was associated. The combined treatment triggered an increased apoptosis compared with either drug tested alone. A significant inhibition of tumor growth and microvessel area was obtained in neuroblastoma-bearing mice when treated with vinblastine or rapamycin alone, and a more dramatic effect with the combined treatment, compared with control mice. The therapeutic effectiveness, expressed as increased life span, was statistically improved by the combined therapy, compared with mice treated with either drug tested separately. Histologic evaluation of primary tumors showed that the combined treatment inhibited proliferation and angiogenesis and induced apoptosis. Combined treatment of neuroblastoma cells and neuroblastoma-bearing mice with vinblastine and rapamycin induced the down-modulation of both vascular endothelial growth factor production and vascular endothelial growth factor receptor 2 expression. In the chorioallantoic membrane assay, angiogenesis induced by humanneuroblastoma biopsy specimens was significantly inhibitedby vinblastine and rapamycin. Conclusions: These results may be relevant to design new therapeutic strategies against neuroblastoma. Neuroblastoma is the most common extracranial solid tumor of infancy (1). Despite of aggressive treatment strategies, such as high-dose chemotherapy and bone marrow transplantation, the prognosis for patients suffering from advanced stage disease has not been improved in a satisfactory manner and neuroblastoma continues to present a formidable clinical challenge (2). Therefore, development of new treatment approaches has been the focus, in the last few years, of many neuroblastoma studies. The Vinca alkaloid vinblastine is a microtubule inhibitor belonging to an important class of chemotherapeutic agents that affect polymerization and stability of microtubules (3). Vinca alkaloids prevent mitotic spindle formation, resulting in a G 2-M phase cell cycle arrest and subsequent apoptotic cell death (4). Vinblastine is mainly used, in combination with other drugs, for therapy of several lymphoid malignancies and some solid pediatric tumors (5, 6). Rapamycin is a lipophilic macrolide antibiotic, originally identified as an anti-fungal agent. Many studies have, however, showed that rapamycin and its derivatives present both immunosuppressant (7, 8) and antitumor properties (9). Rapamycin acts by specifically inhibiting the mammalian target