Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a recent study, we showed that the proteasome inhibitor bortezomib sensitizes human bladder cancer cells to IFN-induced cell death. Here, we characterized the molecular mechanisms underlying the antitumoral effects of the combination in more detail. Bortezomib synergized with IFN-alpha to promote apoptosis via a tumor necrosis factor-related apoptosis-inducing ligand-associated mechanism but did not inhibit production of proangiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) in human UM-UC-5 cells. In contrast, exposure to the combination did not increase the levels of apoptosis in human UM-UC-3 cells but did inhibit the production of basic fibroblast growth factor and vascular endothelial growth factor. Studies with tumor xenografts confirmed that combination therapy with bortezomib plus IFN-alpha was effective in both models but that the effects were associated with differential effects on tumor necrosis factor-related apoptosis-inducing ligand-associated apoptosis (predominant in UM-UC-5) versus inhibition of angiogenesis (predominant in UM-UC-3). Together, our results show that combination therapy with IFN-alpha plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer.
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PMID:Combination therapy with IFN-alpha plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells. 1717 6

A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly, green tea polyphenols, as well as several flavonoids such as genistein, curcumin and resveratrol, have also been shown to have chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.
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PMID:The proteasome as a potential target for novel anticancer drugs and chemosensitizers. 1719 31

Most anticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death. Bortezomib, a specific inhibitor of 26S proteasome, has shown clinical activity in several human tumors, including myeloma. Here we show that the uptake of human myeloma cells by dendritic cells (DCs) after tumor cell death by bortezomib, but not gamma irradiation or steroids, leads to the induction of antitumor immunity, including against primary tumor cells, without the need for any additional adjuvants. The delivery of activating signal from bortezomib-killed tumor cells to DCs depends on cell-cell contact between DCs and dying tumor cells and is mediated by bortezomib-induced exposure of heat shock protein 90 (hsp90) on the surface of dying cells. The combination of bortezomib and geldanamycin (an hsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity. These data identify drug-induced exposure of endogenous heat shock proteins on the surface of dying cells as a mechanism of immunogenic death of human tumors. Specific targeting of bortezomib to tumors may enhance their immunogenicity and the induction of antitumor immunity.
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PMID:Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. 1729 90

Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins. The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB) apparently contributes to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs), which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting human myeloma cell line JK-6L and murine muH-chain-transfected Ag8.H myeloma cells, apoptosis induction upon proteasome inhibition was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor-treated cells. Hence, proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing clinical applications.
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PMID:Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. 1730 21

Bortezomib (Velcade) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2 alpha and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies.
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PMID:TNF potentiates anticancer activity of bortezomib (Velcade) through reduced expression of proteasome subunits and dysregulation of unfolded protein response. 1737 61

A major challenge to broadening oncology applications for inhibitors of the ubiquitin-proteasome system (UPS) is the identification of UPS-dependent cancer pathways predictive of tumors responsive to peptidomimetic inhibitors of its 20S core protease activity. To inform clinical studies evaluating UPS inhibitors as breast cancer therapeutics, seven phenotypically diverse human breast cancer cell line models were characterized for their cellular and molecular responses to the clinically approved 20S inhibitor bortezomib (PS341; Velcade), focusing on those overexpressing estrogen receptor (ER) or ERBB2/HER2, because these oncogenic receptor pathways are constitutively activated in approximately 80% of all breast cancers. All models demonstrated dose-dependent bortezomib reduction in intracellular 20S activity correlating with cell growth inhibition, and bortezomib IC(50) values (concentrations producing 50% growth inhibition) varied directly with pretreatment 20S activities (r = 0.74; *, p < 0.05), suggesting that basal 20S activity may serve as a clinical predictor of tumor responsiveness to UPS inhibition. Reduction in 20S activity (> 60%) was associated with early (24 h) intracellular relocalization of ER (nucleus to cytoplasm) and ERBB2 (plasma membrane to perinuclear lysosomes), buildup of ubiquitinated and Hsp70-associated receptor, degradation and loss of ER and ERBB2 function, and induction of cellular apoptosis. These models were also used to screen a pharmacologic panel of pathway-targeted anticancer agents [4-hydroxy-3-methoxy-5-(benzothiazolylthiomethyl)benzylidenecyanoacetamide (AG825), 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (AZD6244/ARRY142886), 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride (LY294002), 17-N-allylamino-17-demethoxy geldanamycin (17AAG), and (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (LAQ824)] for those capable of sensitizing to bortezomib. In keeping with the observation that 20S reduction has little effect on mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling in either ER-positive or ERBB2-positive models, only the MEK-1/2 inhibitor AZD6244 consistently improved the antitumor activity of bortezomib.
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PMID:Proteasome-regulated ERBB2 and estrogen receptor pathways in breast cancer. 1739 24

Bortezomib is a potent drug for the treatment of multiple myeloma. Its anti-tumor activity is mediated by proteasome inhibition leading to decreased cell proliferation and induction of apoptosis. However, an unimpaired proteasomal function plays a crucial role for the induction of anti-tumor immunity by dendritic cells (DCs), which are currently used for therapeutic vaccination against various tumors including myeloma. In the present study, we investigated the impact of bortezomib on the immunostimulatory capacity of 6-sulfo LacNAc (slan) DCs, which represent a major subset of human blood DCs. We demonstrated that this proteasome inhibitor efficiently impairs the spontaneous in vitro maturation of slanDCs and the release of tumor necrosis factor (TNF)-alpha as well as interleukin (IL)-12 upon lipopolysaccharide (LPS) stimulation. Functional data revealed that bortezomib profoundly inhibits slanDC-induced proliferation and differentiation of CD4(+) T cells. In addition, the capacity of slanDCs to promote interferon-gamma secretion and tumor-directed cytotoxicity of natural killer (NK) cells is markedly impaired by bortezomib. These results provide evidence that bortezomib significantly reduces the ability of native human blood DCs to regulate innate and adaptive anti-tumor immunity and may have implications for the design of therapeutic strategies combining DC vaccination and bortezomib treatment.
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PMID:Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells. 1749 70

The ubiquitin-proteasome pathway plays a central role in the degradation of proteins involved in several pathways including the cell cycle, cellular proliferation and apoptosis. Bortezomib is the first proteasome inhibitor to enter clinical use, and received approval by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma, therefore validating inhibition of the proteasome as an anticancer target. The approval of Bortezomib was based on a large, international, multicenter phase III trial showing its efficacy and safety compared with conventional therapy. Preclinical data also demonstrates the synergistic effect of bortezomib with other chemotherapeutic agents and its ability to overcome drug resistance. Since then several other proteasome inhibitors have been developed. The anti-tumor activities of bortezomib have been attributed to its effect on pro-apoptotic pathways including the inhibition of NF-kappaB and induction of endoplasmic reticulum stress. However, the molecular mechanisms are not fully understood. In this review, we will summarize the molecular mechanism of apoptosis by bortezomib.
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PMID:Targeting the ubiquitin-proteasome pathway in cancer therapy. 1750 61

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in combination with cisplatin or pemetrexed. We used four MPM cell lines (MS589, H28, H2052, JMN), a normal mesothelial cell line (HM3), and a lung cancer cell line (H23) in survival studies utilizing bortezomib, cisplatin, and pemetrexed alone and in combination by administering concurrently or by varying the order of administration. We determined the effect of bortezomib on the cell cycle, apoptosis, and on the expression of cell cycle proteins p21/WAF1 and p27/KIP1 and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. Bortezomib was highly cytotoxic to MPM cells and induced both G(2)/M and G(1)/S cell cycle arrest. Apoptosis increased in a concentration- and time-dependent manner in 3 of 4 MPM cell lines. Bortezomib stabilized or increased protein levels of p21/WAF1 and IAP-1 and to a lesser degree p27/KIP1, IAP-2, XIAP, and survivin. In combination studies with cisplatin, bortezomib was generally synergistic at high concentrations and antagonistic at low concentrations. Bortezomib increased the cytotoxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in MPM patients alone or in combination with standard chemotherapy but the order of administration is likely to be important. This study justifies further evaluation of bortezomib in MPM.
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PMID:Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma. 1752 64

Development of new therapies for myeloma has been hindered by the lack of suitable preclinical animal models of the disease in which widespread tumor foci in the skeleton can be detected reliably. Traditional means of detecting skeletal tumor infiltration such as histopathology are cumbersome and labor-intensive and do not allow temporal monitoring of tumor progression or regression in response to therapy. To resolve this problem, we modified the Radl 5TGM1 model of myeloma bone disease such that fluorescent myeloma tumors can be optically imaged in situ. Here, we show that murine myeloma 5TGM1 tumor cells, engineered to express enhanced green fluorescent protein (eGFP; 5TGM1-eGFP cells), can be imaged in a temporal fashion using a fluorescence illuminator and a charge-coupled device camera in skeletons of live C57BL/KaLwRij mice. High-resolution, whole-body images of tumor-bearing mice revealed that myeloma cells homed almost exclusively to the skeleton, with multiple focal tumor foci in the axial skeleton, consistent with myeloma tumor distribution in humans. Finally, the tested antitumor treatment effect of Velcade (bortezomib), a proteasome inhibitor used clinically in myeloma, was readily detected by GFP imaging, suggesting the power of the technique in combination with the Radl 5TGM1-eGFP model for rapid preclinical assessment and sensitive monitoring of novel and potential therapeutics. Whole-body GFP imaging is practical, convenient, inexpensive, and rapid, and these advantages should enable a high throughput when evaluating in vivo efficacy of new potential antimyeloma therapeutics and assessing response to treatment.
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PMID:Detection of myeloma in skeleton of mice by whole-body optical fluorescence imaging. 1754 Oct 32


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