Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian target of rapamycin (mTOR) pathway plays important roles in regulating nutrient metabolism and promoting the growth and survival of cancer cells, which exhibit increased glycolysis for ATP generation. In this study, we tested the hypothesis that inhibition of the mTOR pathway and glycolysis would synergistically impact the energy metabolism in cancer cells and may serve as an effective therapeutic strategy to kill malignant cells. Using human lymphoma cells and leukemia cells, we demonstrated that the combination of rapamycin, an mTOR inhibitor, with a glycolytic inhibitor produced synergistic cytotoxic effect, as evidenced by apoptosis and cell growth inhibition assays. Mechanistic studies showed that inhibition of the mTOR pathway by rapamycin alone sufficiently suppressed the phosphorylation of the downstream molecules p70S6K and 4E-BP-1, but only caused a moderate cytostatic effect. Combination of mTOR inhibition and blockage of glycolysis synergistically suppressed glucose uptake and severely depleted cellular ATP pools, leading to significant enhancement of cell killing. In contrast, combination of rapamycin and ara-C did not increase cytotoxicity in vitro. Our findings suggest that targeting mTOR pathway in combination with inhibition of glycolysis may be an effective therapeutic strategy for hematological malignancies. This mechanism-based drug combination warrants further investigation in preclinical and clinical settings.
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PMID:Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. 1619 82

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.
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PMID:Kinases as drug discovery targets in hematologic malignancies. 1630 89

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
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PMID:Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. 1643 6

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The Kaposi's sarcoma lesion expresses high levels of angiogenic factors and is comprised of a mixed cell population, including endothelial cells that are infected with KSHV. We find that the KSHV K1 protein is expressed in Kaposi's sarcoma lesions and can immortalize and extend the life span of primary human umbilical vein endothelial cells in culture. Vascular endothelial growth factor (VEGF) is critical for the survival of endothelial cells, and we show that expression of K1 in endothelial cells resulted in increased levels of secreted VEGF and the activation of key signaling pathways, including the VEGF/VEGF receptor and the phosphatidylinositol-3'-OH-kinase (PI3K) pathway. The SH2 binding motifs present in the cytoplasmic tail of K1 were critical for K1's ability to activate these pathways. Activation of PI3K by K1 results in activation of Akt kinase and mammalian target of rapamycin and inactivation of the proapoptotic proteins FKHR, glycogen synthase kinase-3, and Bad, which are events indicative of cell survival. Because activation of the PI3K pathway is critical for transformation of many human cells, we suggest that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. We also report that K1 enhances angiogenesis in vivo and increases tumor vasculature and tumor size.
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PMID:Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus. 1658 91

The authors previously reported the mRNA expression of Glutathione S-transferases theta (GSTT)-1, wild type (623 bp) and mutant (500 bp) in MDS patients. The deletion of 123 bp creates a sequence that is homologues to mammalian target of rapamycin (mTOR). To analyse the function of mutant GSTT-1 gene, stable transformants for the mutant and wild-type GSTT-1 gene, respectively, were established. In this study, the expression of wild and mutant type GSTT-1 gene of those stable transformants and bone marrow cells from MDS patients by RT-PCR was observed in the presence or absence of rapamycin. In result, exposure of rapamycin led to the disappearance of just the mutant gene band. This phenomenon possibly indicates that rapamycin only attacked the mutant GSTT-1 expressing clone.
Leuk Lymphoma 2006 May
PMID:Possible molecular target therapy with rapamycin in MDS. 1675 77

Diffuse large B-cell lymphoma (DLBCL) is a common lymphoma entity. Although a significant amount of DLBCL patients can be cured with modern chemotherapeutic regimens, a substantial proportion of patients die because of progressive disease. Therefore, new therapeutic strategies are clearly needed. Inhibitors of mTOR [mammalian target of rapamycin (Rap)] represent a new class of antiproliferative drugs with applications as immunosuppressive and anticancer agents. Extensive safety data exist on the mTOR inhibitor RAD001, which is already approved as an immunosuppressant in organ transplant recipients. Rap and RAD001 inhibited cell cycle progression in DLBCL cells by inducing a G1 arrest without inducing apoptosis. Phosphorylation of the main targets of mTOR, p70 s6 kinase and 4-EBP-1 was reduced in cells cultured in the presence of RAD001. Cell cycle arrest was accompanied by reduced phosphorylation of the retinoblastoma protein (RB) as well as reduced expression of cyclin D3 and A in all cell lines. Although the effect of the chemotherapeutic agent vincristine (vin) was not enhanced by RAD001, rituximab-induced cytotoxicity was augmented in the rituximab-sensitive cell lines. mTOR inhibition is a promising therapeutic strategy in DLBCL by inducing a G1 arrest and augments rituximab-induced cytotoxicity. Therefore, combination of these drugs might be an interesting new therapeutic approach in DLBCL patients.
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PMID:Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. 1685 92

The phosphatidylinositol-3-OH kinase [PI(3)K] pathway is frequently activated in human cancers and represents a rational target for therapeutic intervention. We have previously shown that enforced expression of Akt, which is a downstream effector of PI(3)K, could promote tumorigenesis and drug resistance in the Emu-myc mouse lymphoma model, and that these tumors were particularly sensitive to inhibition of mammalian target of rapamycin (mTOR) with rapamycin when combined with conventional chemotherapy. We now show that reduced dosage of PTEN, a negative regulator of PI(3)K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model. Nonetheless, loss of even one PTEN allele resulted in lymphomas that were resistant to conventional chemotherapy yet sensitive to rapamycin/chemotherapy combinations. These effects could be recapitulated by using RNA interference to suppress PTEN expression in lymphomas, which were previously established in the absence of PI(3)K lesions. Finally, the introduction of lesions that act downstream of mTOR (eIF4E) or disable apoptosis (Bcl-2 and loss of p53) into PTEN+/- lymphomas promoted resistance to rapamycin/chemotherapy combinations. Thus, whether activation of the PI(3)K pathway confers sensitivity or resistance to therapy depends on the therapy used as well as secondary genetic events. Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic.
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PMID:Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. 1688 64

The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycin-sensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD- and PI3K-independent pathways. Finally, Syk inhibition by piceatannol or by siRNA plasmids resulted in a potent inhibition of mTOR activity in FL cells, as well as in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma. These findings suggest that the Syk-mTOR pathway has a critical function in FL survival, and therefore, that Syk could be a promising new target for B-lymphoma therapy.
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PMID:Syk-dependent mTOR activation in follicular lymphoma cells. 1691 21

The phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.
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PMID:Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. 1691 89

The antitumor potency of the mTOR inhibitor rapamycin (sirolimus) is the subject of intense investigations. Primary effusion lymphoma (PEL) appears as an AIDS-defining lymphoma and like Kaposi sarcoma has been linked to Kaposi sarcoma-associated herpesvirus (KSHV). We find that (1) rapamycin is efficacious against PEL in culture and in a murine xenograft model; (2) mTOR, its activator Akt, and its target p70S6 kinase are phosphorylated in PEL; (3) rapamycin inhibits mTOR signaling as determined by S6 phosphorylation; (4) KSHV transcription is unaffected; (5) inhibition of IL-10 signaling correlates with drug sensitivity; and (6) addition of exogenous IL-10 or IL-6 can reverse the rapamycin growth arrest. This validates sirolimus as a new treatment option for PEL.
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PMID:Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. 1708 22


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