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)

The dermatotoxicity of arsenic is well established and epidemiological studies identify an increased incidence of keratinocytic tumors (basal cell and squamous cell carcinoma) associated with arsenic exposure. Little is known about the underlying mechanisms of arsenic-mediated skin carcinogenesis, but activation of mitogen-activated protein (MAP) kinases and subsequent regulation of downstream target genes may contribute to tumor promotion and progression. In this study, we investigated activation of the extracellular signal regulated kinase (ERK) and the stress-associated kinase p38 by arsenite in HaCat cells, a spontaneously immortalized human keratinocyte cell line. Arsenite concentrations > or =100 microM stimulate rapid activation of p38 and ERK MAP kinases. However, upon extended exposure (24 h), persistent stimulation of p38 and ERK MAP kinases was detected at low micromolar concentrations of arsenite. Although ERK and p38 were activated with similar time and concentration dependence, the mechanism of activation differed for these two MAP kinases. ERK activation by arsenite was fully dependent on the catalytic activity of the epidermal growth factor (EGF) receptor and partially dependent on Src-family kinase activity. In contrast, p38 activation was independent of EGF receptor or Src-family kinase activity. Arsenite-stimulated MAP kinase signal transduction resulted in increased production of matrix metalloproteinase (MMP)-9, an AP-1 regulated gene product. MMP-9 induction by arsenite was prevented when EGF receptor or MAP kinase signaling was inhibited. These studies indicate that EGF receptor activation is a component of arsenite-mediated signal transduction and gene expression in keratinocytes and that low micromolar concentrations of arsenite stimulate key signaling pathways upon extended exposure. Stimulation of MAP kinase cascades by arsenic and subsequent regulation of genes including c-fos, c-jun, and the matrix degrading proteases may play an important role in arsenic-induced skin carcinogenesis.
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PMID:Roles of mitogen activated protein kinases and EGF receptor in arsenite-stimulated matrix metalloproteinase-9 production. 1550 54

Arsenic trioxide (ATO) has been implicated as a promising anticancer agent by inhibiting cell growth and inducing apoptosis in certain types of cancer cells. This study explored the antimetastasis property of arsenic, drew potential link between arsenic use and radiotherapy, and uncovered the specific mechanisms underlying these remarkable responses. Using gelatin invasion assay and intravasation assay, we report the novel finding that low-dose ATO (1 muM) reduced the intrinsic migration ability of HeLa cells and significantly inhibited radiation-promoted tumor invasive potential of CaSki cells without inducing apoptotic cell death. Using the murine Lewis lung carcinoma model, the control animals and ATO treatment animals (1 mg/kg i.p., twice weekly) displayed similar in vivo growth kinetics, whereas the radiation (30 Gy in one fraction) and concurrent treatment groups showed considerable growth inhibition. Importantly, although concurrent treatment did not enhance the effectiveness of radiation therapy to the primary tumor, further examination of the lungs revealed that all animals succumbed to radiation-accelerated lung metastases could be effectively treated by combination of ATO and radiation. Radiation-induced matrix metalloproteinase-9 (MMP-9) expression was significantly inhibited by ATO using sequential analysis of the expression of MMPs in xenografts. Supporting this observation, ATO directly downregulates radiation-induced MMP-9 mRNA expression by inhibiting nuclear factor kappaB activity in human cervical cancer cells. In sum, concurrent arsenic-radiation therapy not only achieves local tumor control but also inhibits distant metastasis. Experimental results of this study highlight a novel strategy in cancer treatment.
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PMID:Arsenic trioxide prevents radiation-enhanced tumor invasiveness and inhibits matrix metalloproteinase-9 through downregulation of nuclear factor kappaB. 1553 21

High-dose therapy with stem cell transplantation (SCT) and novel targeted therapies (thalidomide, its more potent analogues, and bortezomib) represent two approaches for overcoming resistance of multiple myeloma (MM) cells to conventional therapies. While it is now clear that dose-intensification improves the outcome in younger patients, long-term remissions are obtained in a minority of patients. Therefore, the impact of novel agents as part of front-line therapy is the objective of ongoing trials. Gene expression profiling (GEP) will help to improve the management of MM not only by identifying prognostic subgroups but also by defining molecular pathways that are associated with these subgroups and that are possible targets for future therapies. In Section I, Dr. John Shaughnessy describes recent data obtained with GEP of CD138-purified plasma cells from patients with MM. His group has already shown that overexpression of the Wnt signaling inhibitor DKK1 by MM plasma cells blocks osteoblast differentiation and contributes to the development of osteolytic bone lesions. Recent data allow identification of four subgroups of MM in which GEP is highly correlated not only with different clinical characteristics and outcome but also with different cytogenetic abnormalities. In addition, abnormal expression of only three genes (RAN, ZHX-2, CHC1L) is associated with rapid relapses. In the context of intensive therapy with tandem autotransplantations, this model appears to be more powerful than current prognostic models based on standard biologic variables and cytogenetics. Understanding why the dysregulation of these three genes is associated with a more aggressive behavior of the disease will help to define new therapeutic strategies. In Section II, Dr. Jean-Luc Harousseau presents recent results achieved with tandem autologous SCT (ASCT) and with reduced intensity conditioning (RIC) allogeneic SCT. ASCT is now considered as the standard of care in patients up to 65 years of age. The IFM (Intergroupe Francophone du Myelome) has recently shown that double ASCT is superior to single ASCT. Current results of three other randomized trials confirm that double ASCT is superior, at least in terms of event-free survival. However, patients with poor prognostic features do poorly even after tandem ASCT. Strategies to further improve the outcome of ASCT include more intensive therapies and the use of novel agents such as thalidomide and immunomodulatory analogs (IMiDs) or bortezomib. Results of allogeneic SCT remain disappointing in MM even with T cell-depleted grafts. Preliminary results of a strategy combining ASCT to reduce tumor burden and RIC allogeneic SCT are encouraging, although the follow-up is still short. However, again, patients with chromosome 13 deletions have poor results with RIC. Longer follow-up of ongoing multicentric studies will help to clarify the indications of RIC. In Section III, Dr. Paul Richardson summarizes current knowledge of novel targeted therapies in MM. A better understanding of interactions between MM cells and bone marrow stromal cells and of the signaling cascades whereby cytokines mediate proliferation, survival, drug resistance and migration of MM cells provide the rationale for testing novel agents in relapsed/refractory MM. Increased angiogenesis coupled with the known anti-angiogenesis activity of thalidomide justified its use in refractory MM. The remarkable responses initially achieved prompted a number of clinical studies in different indications and the development of more potent IMIDs. Among them CC-5013 (Revlimid) has been tested in Phase I/II studies and a randomized Phase III study has just been completed. Blockade of NF-kappa B using the proteasome inhibitor bortezomib (Velcade) may mediate anti-MM activity by inhibiting interleukin (IL)-6 production in stromal cells and other mechanisms of action have been shown in preclinical studies. Based on the promising results of the Phase II trial, a large randomized trial of bortezomib versus dexamethasone has been completed. Studies of bortezomib combined with other drugs are ongoing. Arsenic trioxide has a number of properties showing that it targets MM cells interacting with the microenvironment. Clinical studies are ongoing as well. Other agents in MM have already been or will probably be translated soon from the bench to the bedside.
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PMID:Multiple myeloma. 1556 86

Arsenic trioxide is a potent chemotherapeutic agent by virtue of its ability to selectively trigger apoptosis in tumor cells. Previous studies have demonstrated that arsenicals cause direct damage to mitochondria, but it is not clear that these effects initiate apoptosis. Here we used Bak-/- mouse liver mitochondria and virally immortalized Bax-/- Bak-/- mouse embryonic fibroblasts (MEFs) to investigate whether or not multidomain proapoptotic BCL-2 family proteins were required for arsenic-induced mitochondrial damage and cell death. At clinically achievable concentrations, arsenic stimulated cytochrome c release and apoptosis via a Bax/Bak-dependent mechanism. At higher concentrations (125 microM-1 mM), cells died via a Bax/Bak-independent mechanism mediated by oxidative stress that resulted in necrosis. Consistent with previous reports, arsenic directly inhibited complex I of the mitochondrial electron transport chain, which resulted in mitochondrial permeability transition (MPT), accompanying generation of reactive oxygen species (ROS), and thiol oxidation. However, these effects only occurred at concentrations of arsenic trioxide of 50 microM and higher, and the oxidative stress associated with these effects blocked caspase activation. Our data demonstrate for the first time that the cytochrome c release which initiates apoptosis in cells exposed to this classic mitochondrial poison occurs indirectly via the activation of Bax/Bak rather than via direct mitochondrial damage. Furthermore, the results implicate reactive oxygen species in a concentration-dependent mechanistic switch between apoptosis and necrosis.
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PMID:Indirect effects of Bax and Bak initiate the mitochondrial alterations that lead to cytochrome c release during arsenic trioxide-induced apoptosis. 1584 91

Arsenic is a well-known carcinogen for human skin, but its mechanism of action and proximal macromolecular targets remain to be elucidated. In the present study, low micromolar concentrations of sodium arsenite maintained the proliferative potential of epidermal keratinocytes, decreasing their exit from the germinative compartment under conditions that promote differentiation of untreated cells. This effect was observed in suspension and in post-confluent surface cultures as measured by colony-forming ability and by proportion of rapidly adhering colony-forming cells. Arsenite-treated cultures exhibited elevated levels of beta1-integrin and beta-catenin, two proteins enriched in cells with high proliferative potential. Levels of phosphorylated (inactive) glycogen synthase kinase 3beta were higher in the treated cultures, likely accounting for the increased levels of transcriptionally available beta-catenin. These findings suggest that arsenic could have co-carcinogenic and tumor co-promoting activities in the epidermis as a result of increasing the population and persistence of germinative cells targeted by tumor initiators and promoters. These findings also identify a critical signal transduction pathway meriting further exploration in pursuit of this phenomenon.
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PMID:Arsenite maintains germinative state in cultured human epidermal cells. 1605 1

Arsenic trioxide (As(2)O(3)), a valuable anticancer drug for the treatment of acute promyelocytic leukemia, may also have therapeutic potential for the treatment of solid tumors. However, its therapeutic efficacy against solid tumors is lacking even at high dosages. Other therapeutic strategies are required to enhance the efficacy of As(2)O(3) against solid tumors such as hepatocellular carcinoma (HCC), which is refractory to chemotherapy. B7H3, a new member of the B7 family, has been shown to induce antitumor immunity. Intratumoral injection of B7H3 plasmids eradicates small EL-4 lymphomas, but monotherapy is ineffective against large tumors. Here we investigated whether As(2)O(3) would synergize with B7H3 immunotherapy to combat HCC. Large subcutaneous H22 HCCs (0.7-0.8 cm in diameter) established in BALB/c mice were rapidly and completely eradicated when intratumoral administration of As(2)O(3) was preceded by in situ gene transfer of B7H3. In contrast, neither As(2)O(3) nor B7H3 monotherapy was effective. The antitumor activity of As(2)O(3) was attributed to increased tumor-cell apoptosis, perhaps as a result of direct cytotoxicity as well as decreased tumor angiogenesis. Combination therapy generated potent systemic antitumor immunity mediated by CD8(+) and NK cells that was effective in combating a systemic challenge of 1 x 10(7) parental H22 cells. It led to the simultaneous and complete regression of multiple distant tumor nodules, concomitant with increased levels of serum IFN-gamma and cytotoxic T lymphocyte (CTL) activity. In conclusion, combining B7H3-mediated immunotherapy with As(2)O(3) warrants investigation as a therapeutic strategy to combat HCC, and other malignancies.
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PMID:Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas. 1621 49

Arsenite is a well known metalloid human carcinogen, and epidemiological evidence has demonstrated its association with the increased incidence of lung cancer. However, the mechanism involved in its lung carcinogenic effect remains obscure. The current study demonstrated that exposure of human bronchial epithelial cells (Beas-2B) to arsenite resulted in a marked induction of cyclooxygenase (COX)-2, an important mediator for inflammation and tumor promotion. Exposure of the Beas-2B cells to arsenite also led to significant transactivation of nuclear factor of activated T-cells (NFAT), but not activator protein-1 (AP-1) and NFkappaB, suggesting that NFAT, rather than AP-1 or NFkappaB, is implicated in the responses of Beas-2B cells to arsenite exposure. Furthermore, we found that inhibition of the NFAT pathway by either chemical inhibitors, dominant negative mutants of NFAT, or NFAT3 small interference RNA resulted in the impairment of COX-2 induction and caused cell apoptosis in Beas-2B cells exposed to arsenite. Site-directed mutation of two putative NFAT binding sites between-111 to +65 in the COX-2 promoter region eliminated the COX-2 transcriptional activity induced by arsenite, confirming that those two NFAT binding sites in the COX-2 promoter region are critical for COX-2 induction by arsenite. Moreover, knockdown of COX-2 expression by COX-2-specific small interference RNA also led to an increased cell apoptosis in Beas-2B cells upon arsenite exposure. Together, our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and AP-1- or NFkappaB-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells.
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PMID:Cyclooxygenase-2 induction by arsenite is through a nuclear factor of activated T-cell-dependent pathway and plays an antiapoptotic role in Beas-2B cells. 3154 Oct 29

Arsenic trioxide (As2O3) is a potent antitumor agent used to treat acute promyelocytic leukemia (APL) and, more recently, solid tumors. However, the dose of As2O3 required to suppress human xenographs in mice is markedly higher than that used to treat APL in humans. Paradoxically, low doses of As2O3 stimulate angiogenesis, which might be expected to promote tumor growth. Clearly, appropriate dosages of As2O3 are required to treat human patients to avoid toxicity and undesirable side effects. In the present study, we investigated As2O3 with respect to its toxicity and effects on tumor growth, angiogenesis and cell apoptosis using H22 hepatocellular carcinoma (HCC) cells in a mouse model of HCC. As2O3 inhibited tumor growth and angiogenesis, and enhanced tumor cell apoptosis at doses greater than 1 mg/kg, but mice lost weight and failed to thrive at doses of 4 mg/kg and greater. In contrast, low doses (<1 mg/kg) of As2O3 promoted tumor growth, upregulated the expression of vascular endothelial growth factor and tumor angiogenesis, and had no effect on tumor cell apoptosis. In vitro studies demonstrated that As2O3 inhibited the proliferation of H22 tumor cells and bovine aortic endothelial cells, and induced their apoptosis in a dose- and time-dependent fashion, suggesting that the mechanism of As2O3-mediated inhibition of tumor growth is due to direct effects of the drug on both tumor cells and endothelia. In summary, different doses of As2O3 have opposing effects on tumor growth and angiogenesis. The results demonstrate that As2O3 has a narrow window of therapeutic opportunity with respect to dosage, and that low doses of the drug as used in metronomic therapy should be used with extreme caution.
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PMID:Opposing effects of arsenic trioxide on hepatocellular carcinomas in mice. 1682 9

Arsenic trioxide (ATO) is a potent anti-leukemic chemotherapeutic agent for acute promyelocytic leukemia (APL) that results from a t (15, 17) chromosomal translocation that produces PML-RARalpha, a fusion protein between a tumor suppressor PML and the retinoic acid receptor RARalpha. APL patients are initially treated with retinoic acid, but most develop resistance and relapse. In contrast, ATO induces prolonged remissions even in the relapsed cases. However, the molecular mechanisms by which ATO kills the leukemic cells are not fully understood. We find that ATO induces apoptosis, at least in part, by activating proapoptotic kinase Chk2. ATO does this by stimulating ATR (ataxia telangiectasia mutated and Rad3-related) kinase, a Chk2-activating kinase. In conjunction, ATO degrades PML-RARalpha, resulting in the restoration of PML, which is required for autophosphorylation and full activation of Chk2. As a result, the p53-dependent apoptosis pathway is activated. Based on this, we propose that a pathway composed of ATR, PML, Chk2, and p53 plays a role in ATO-mediated apoptosis, a notion that is consistent with the observation that Chk2 is genetically intact and mutations in the p53 gene are extremely rare in APL.
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PMID:ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis. 1689 16

Arsenic trioxide (ATO, As2O3) is emerging as a front line agent for treatment of acute promyelocytic leukemia with giving a complete remission rate of 83-95%. ATO also shows significant activity in relapsed/refactory multiple myeloma; however, efforts to expand clinical utility to other cancers have been limited by its toxicity profile at higher doses. New bioavailable, liposome encapsulated As(III) materials exhibit a significantly attenuated cytotoxicity that undergoes pH-triggered release of an active drug. The arsenic drugs are loaded into 100-nm-scale liposomes at high concentration (>270 mM) and excellent retention (shelf life > 6 months at 4 degrees C), as determined by inductively coupled plasma optical emission spectroscopy (ICP-OES), transmission electron microscopy (TEM), and energy-dispersive X-ray (EDX) diffraction. In the loading mechanism, arsenous acid crosses the bilayer membrane in exchange for acetic acid and an insoluble transitional metal (e.g., Ni2+, Co2+) arsenite salt is formed. The resultant liposomal arsenic nanoparticles appear to be stable in physiological situations but release the drug cargo in a lower pH environment, as encountered in intracellular endosomes. These drugs exhibit attenuated cytotoxicities against human lymphoma tumor cells compared with that of free As2O3. Controlled release of arsenic drugs, and hence control of toxicity, is feasible with this system. The results demonstrate that cytotoxicity can be controlled via transitions of the inorganic drug between solid and solution phases and suggest a mechanism for further improvement of the risk/benefit ratio of As2O3 in treatment of a variety of cancers.
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PMID:Lipid encapsulation of arsenic trioxide attenuates cytotoxicity and allows for controlled anticancer drug release. 1703 34


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