Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha; MR(1)) and its binding site, the epidermal growth factor receptor (EGFR; MR(2)), have proven efficacious against PC-3 and LNCaP prostate tumors when evaluated in both in vitro and in vivo models. To enhance their activity, and also to introduce a significantly different type of multifunctional agent into this field, "bispecific" oligos were constructed containing truncated sequences (derived from MR(1) and MR(2)) recognizing both TGF-alpha and EGFR mRNA internal binding sites, located about their respective AUG initiation codons. Two bispecifics were constructed, each having complementary sequences for TGF-alpha and EGFR mRNA, but differing in their 5' to 3' tandem orientation (TGF-alpha/EGFR [MR(12)] and EGFR/TGF-alpha [MR(21)] sequences). These bispecifics were tested in an in vitro system against PC-3 and LNCaP prostate tumor cells, with comparisons made to the original monospecific oligos from which they were derived. Efficacy was also compared when administered either alone or in combination with conventional chemotherapeutic agents. The purpose of this study was: 1) to validate the concept that these newly developed bispecific oligos have antitumor activity; 2) to enhance their efficacy through combination therapy; 3) to identify differences in effectiveness dependent upon binding site orientation; 4) identification of a dominant binding site that can be used to design other bispecifics that target additional tumor regulatory pathways. When fully evaluated against PC-3 cells in a series of experiments, newly developed bispecific oligos are at least as effective as their monospecific counterparts from which they were derived, and the bispecific with the MR(21) orientation is notably more effective than the MR(1) monospecific by 64% (p = 0.014 by Student t-test and p = 0.068 by the more stringent Mann-Whitney U test). Bispecifics were more effective when administered with chemotherapeutics (producing inhibition of 52.1% and 61.2% for MR(12) and MR(21), respectively, with Cytoxan (cyclophosphamide) inhibition of 59.0% and 65.1% for MR(12) and MR(21), respectively, with Taxol (paclitaxel) and 63.0% and 69.4% for MR(12) and MR(21), respectively, with DES [diethylstilbestrol]). Increasing the oligo concentration above 6.25 microM with cyclophosphamide had no additional effect. The sequence directed against EGFR was dominant and contributed most to bispecific activity, particularly when inserted 5' to the TGF-alpha binding sequence (MR(21) orientation). Bispecific oligos are a significant advance in the design of antisense compounds and could play a role in treating prostate cancer, particularly when they are administered with traditional chemotherapeutics. The truncated portion of the MR(2) oligo used here should be included when constructing second-generation bispecifics that target proteins associated with other regulatory pathways, such as apoptosis.
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PMID:Bispecific antisense oligonucleotides with multiple binding sites for the treatment of prostate tumors and their applicability to combination therapy. 1713 30

We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC50 = 0.05 micromol/l in CPA, 0.03 micromol/l in APA). Therefore, we tried to develop a novel and effective PDGF-betaR inhibitor by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with manganese(IV) oxide (MnO2) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC50 = 0.014 micromol/l in CPA, 0.007 micromol/l in APA) and selective [IC50 values against vascular endothelial growth factor receptor 2 (VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth factor receptor) and insulin growth factor I receptor (IGF-IR)/IC50 against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC50 = 0.004 micromol/l in CPA, 0.0008 micromol/l in APA, KDR: IC50 = 0.008 micromol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.
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PMID:Potent platelet-derived growth factor-beta receptor (PDGF-betaR) inhibitors: Synthesis and structure-activity relationships of 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one derivatives. 1726 99

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, may have a potentiality as a structural template for rational drug design in killing cancer cells. Treatment of K562 cells with 0.3 microM of CTX III resulted in G2/M phase cell cycle arrest that was associated with a marked decline in protein levels of G2/M regulatory proteins including cyclin A, cyclin B1, Cdk2 and Cdc25C. In contrast to no effect on the phosphorylation of ERK, p38 MAPK and Akt, an activation of JNK was noted when K562 cells were exposed to CTX III. CTX III-mediated G2/M phase arrest and apoptosis were reduced by treatment with the JNK-specific inhibitor SP600125, but not by ERK and p38MAPK inhibitors. Further investigation showed that the specific JNK inhibitor, SP600125, reduced the activation of caspase-3, caspase-9, and reversed the decline in the expression of cyclin B1. Taken together, our data show for the first time that JNK, but not ERK, p38MAPK or Akt signaling, plays an important role in CTX III-mediated G2/M arrest and apoptosis in K562 cancer cells.
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PMID:Involvement of c-jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by cardiotoxin III (Naja naja atra) in K562 leukemia cells. 1736 2

Taxanes (TX) were administered to 246 of 292 patients with recurrent/metastatic breast cancer (MBC) who were treated in Hiei Hospital between January 2001 and May 2006. Recently, TX has been increasingly prescribed for preoperative treatment and postoperative adjuvant therapy. To improve the prognosis of MBC, regimens effective for TX-resistant cancer patients should be developed. In this study, with respect to hormone receptor (HR) and Her 2/neu (HER 2), we retrospectively investigated whether our series responded to the regimens used after TX resistance was acquired. As post TX-resistance therapy (trastuzumab was combined in HER2-positive patients), 387 treatment regimens were administered to 166 patients. The following regimens achieved a response rate (patients achieving PR or CR/patients who could be evaluated) of 10% or more: combination therapy with TX and capecitabine (11/61, 18%), CPT-11 (10/57, 17.5%), vinorelbine (5/46, 10.9%), MFL-P (continuous treatment with MTX, 5-FU, LV, and CDDP) (12/47, 25.5%), and DMpC (5'-DFUR, MPA, CPA p.o.) (5/16, 31.2%). The latter 2 regimens achieved a high response rate,and some HR (-) and HER 2 (-) patients also responded to these regimens. In HR (+) or HER 2 (+) patients who responded to TX, survival was longer than that of non-responders. However, there was no difference in the treatment responsiveness of post-TX regimens between TX-responders and non-responders, suggesting the survival-prolonging effect of TX.
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PMID:[Evaluation of therapeutic regimens for taxane-resistant recurrent/metastatic breast cancer]. 1763 40

In previous studies we demonstrated that antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha [MR1]), its binding site the epidermal growth factor receptor (EGFR [MR2]), and the anti-apoptosis protein bcl-2 (MR4) are efficacious against prostate tumors. In recent reports we also describe how two of these mRNA directed binding sites can be synthesized sequentially within a single linear complementary strand and administered either in the presence or absence of additional therapeutic agents. In these continuing experiments "bispecific" oligo pairs were further evaluated in the presence or absence of Cytoxan, Taxol, or DES. One oligo pair recognized the binding sites for TGF-alpha and EGFR mRNA (TGF-alpha/EGFR [MR12] and EGFR/TGF-alpha [MR21]); another pair recognized binding sites for EGFR and bcl-2 (EGFR/bcl-2 [MR24] and bcl-2/EGFR [MR42]). Oligo pairs differ in their linear 5' to 3' binding site orientations, and were tested in vitro against PC-3 and LNCaP prostate tumor cell lines. Following cell attachment, incubations were for 2 days with the agents followed by 2 days in their absence. When tested against PC-3 cells and combined with LD50 Cytoxan, MR2, MR4, MR24, MR42 significantly inhibited 47.3, 45.7, 68.3, and 64.9%; with LD50 Taxol MR2, MR4, MR24, MR42 significantly inhibited 49.8, 45.8, 64.1, and 59.2%; and with LD50 DES MR2, MR4, MR24, MR42 significantly inhibited 66.6, 67.6, 64.3, and 67.2% respectively. Each agent significantly increased the inhibition produced by either oligo alone.LNCaP cells were also incubated with mono- and bispecific oligos in either the presence or absence of chemotherapeutics. MR2, MR4, MR24, MR42 produced significant inhibitions of 57.4, 58.4, 69.4, and 68.6% with LD50 Cytoxan; 70.4, 70.1, 73.6, and 74.0% with LD50 Taxol; and 49.8, 50.1, 59.6, and 53.9%, respectively with LD50 DES.A complete PC-3 experiment compared MR1, MR2, MR4, MR12, MR21, MR24 and MR42, in the presence of LD50 Cytoxan. Each oligo combined with Cytoxan significantly inhibited: MR1 by 51.0, MR2 by 55.0, MR4 by 58.0; MR12 by 56.0; MR21 by 61.1, MR24 by 65.5 and MR42 by 66.0%. Bispecifics directed against two different pathways, MR24, and MR42 were the most effective.A complete LNCaP experiment compared the same series of oligos also in the presence of LD50 Cytoxan. Each oligo combined with Cytoxan significantly inhibited: MR1 by 49.0, MR2 by 50.0, MR4 by 53.0; MR12 by 52.0; MR21 by 58.6, MR24 by 53.9 and MR42 by 58.0%.
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PMID:Combination chemotherapy employing bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors. 1791 84

In the United States, 211,000 women are diagnosed each year with breast cancer. Of the 42,000 breast cancer patients who overexpress the HER2 growth factor receptor, <35% are responsive to treatment with the HER2-disabling antibody, called trastuzumab (Herceptin). Despite those statistics, women diagnosed with breast cancer are now tested to determine how much of this important growth factor receptor is present in their tumor because patients whose treatment includes trastuzumab are three-times more likely to survive for at least 5 years and are two-times more likely to survive without a cancer recurrence. Unfortunately, even among the group whose cancers originally respond to trastuzumab, 25% of the metastatic breast cancer patients acquire resistance to trastuzumab within the first year of treatment. Follow-on "salvage" therapies have prolonged life for this group but have not been curative. Thus, it is critically important to understand the mechanisms of trastuzumab resistance and develop therapies that reverse or prevent it. Here, we report that molecular analysis of a cancer cell line that was induced to acquire trastuzumab resistance showed a dramatic increase in the amount of the cleaved form of the MUC1 protein, called MUC1*. We recently reported that MUC1* functions as a growth factor receptor on cancer cells and on embryonic stem cells. Here, we show that treating trastuzumab-resistant cancer cells with a combination of MUC1* antagonists and trastuzumab, reverses the drug resistance. Further, HER2-positive cancer cells that are intrinsically resistant to trastuzumab became trastuzumab-sensitive when treated with MUC1* antagonists and trastuzumab. Additionally, we found that tumor cells that had acquired Herceptin resistance had also acquired resistance to standard chemotherapy agents like Taxol, Doxorubicin, and Cyclophosphamide. Acquired resistance to these standard chemotherapy drugs was also reversed by combined treatment with the original drug plus a MUC1* inhibitor.
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PMID:MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. 1983

A 34-year-old woman carrying a BRCA1 gene and a significant family history was diagnosed with T1c, N1 breast cancer. The tumor was estrogen receptor, progesterone receptor, and HER-2/Neu negative. The patient received dose-dense chemotherapy with Adriamycin and Cytoxan followed by Taxol, and left breast irradiation. Later, a bilateral S-GAP flap reconstruction with right prophylactic mastectomy and left mastectomy were performed. During her treatment, the patient had an integrative medicine consultation and was seen by a team of health care providers specializing in integrative therapies, including integrative nutrition, therapeutic massage, acupuncture, and yoga. Each modality contributed unique benefit in her care that led to a satisfactory outcome for the patient. A detailed discussion regarding her care from each modality is presented. The case elucidates the need for integrative approaches for cancer patients in a conventional medical setting.
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PMID:Integrative Tumor Board: a case report and discussion from Dana-Farber Cancer Institute. 1981 93

Cyclophosphamide (CP) has been used as an antitumour agent or immunosuppressant clinically, though the potential biological role of CP in the central nervous system (CNS) has not been clarified. In the present study, we found that pretreatment with CP prevented neuronal cell death caused by serum deprivation in cultured cortical neurons. Interestingly, CP stimulated activation of PI3K (phosphatidylinositol 3 kinase) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathways, which are known as survival-promoting intracellular signalings. Furthermore, CP increased the expression of Bcl2, an anti-apoptotic factor. In the presence of inhibitors for PI3K or MAPK/ERK pathways, the CP-dependent neuronal survival and Bcl-2 up-regulation were both abolished. Importantly, significant increase in BDNF (brain-derived neurotrophic factor) expression was induced by CP application, implying that BDNF up-regulation is involved in the CP effect. We propose that CP has a protective effect on CNS neurons via the activation of intracellular signalings, and up-regulation of Bcl2 and BDNF.
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PMID:Cyclophosphamide promotes cell survival via activation of intracellular signaling in cultured cortical neurons. 2005 30

Cardiotoxin III (CTX III), a basic polypeptide with 60-amino acid residues isolated from Naja naja atra venom, has been reported to have cytotoxic activity. CTX III exerted cytotoxicity with the S-phase cell cycle arrest, correlated with a marked decrease in the expression levels of cyclin A, cyclin B, and cyclin-dependent kinase 1 (CDK1), and apoptosis, accompanied with Bax and Bad up-regulation, and the down-regulation of Bcl-2, p-Bad, and X-linked inhibitor of apoptosis (XIAP) with cytochrome c release and sequential activation of caspase-9 and caspase-3 in Ca9-22 cells. Mechanistic studies showed that CTX III suppressed the phosphorylation of Src, EGFR, STAT3, STAT5, Akt, and activation of PI3 K (p110). Moreover, Src inactivation was observed earlier than that of the EGFR and the Src inhibitor PP2 suppressed the levels of phospho-EGFR, phospho-STAT3, phospho-STAT5, phospho-Akt, and PI3 K(p110). The PP2 also caused the S-phase arrest and apoptosis, and led to down-regulation of Bcl-2, p-Bad, XIAP, cyclin A, cyclin B, and CDK1, and up-regulation of Bax and Bad, similar to that observed in CTX III treatment. Taken together, these results indicate that CTX III induces apoptosis and S-phase arrest in Ca9-22 cells via concomitant inactivation of the Src, EGFR, STAT3, STAT5, PI3 K(p110), and Akt signaling pathways.
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PMID:Taiwan cobra cardiotoxin III inhibits Src kinase leading to apoptosis and cell cycle arrest of oral squamous cell carcinoma Ca9-22 cells. 2049 3

The so-called triple-negative (TN) metastatic breast cancer (MBC), that is, MBC expressing no hormone receptors or HER2 protein, has attracted attention because of its low response rate to drug therapy and poor prognosis after recurrence. Of 423 MBC patients in our hospital in and after 2001, 54 had TN tumors. The median survival time (MST) of TN patients (25 months) was shorter than the MSTs of HR (+)/HER2 (-), HR (+)/HER2 (+), and HR (-)/HER2 (+) patients (69, 58, and 39 months, respectively). A retrospective analysis of responses to 162 regimens in 54 TN-MBC patients showed that anthracycline regimens produced a response rate of 18. 8% (a PR or higher response in 3 of 16 patients), whereas a taxane regimen yielded a very low response rate of 8. 1% (3/37). A similar low response was observed in monotherapy with MTX, CPT-11, VNR, gemcitabine, or S-1. Of particular note were the high response rate (46. 2%, 12/26) of DMpC therapy (oral 5'-DFUR, MPA, and CPA) and that (28%, 7/25) of MFL-P therapy (MTX, 5-FU, leucovorin, and CDDP), although these were not standard therapies. In addition, the molecular-targeted drug bevacizumab or cetuximab was concomitantly used with chemotherapeutic agents in 3 patients, and 1 each treated with either therapy achieved a PR. Thus, in the future, we can expect further advances in molecular-targeted therapy while using DMpC and MFL-P for the treatment of TN-MBC as an early-line therapy.
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PMID:[Effective therapeutic regimens for patients with triple-negative (ER/PgR/HER2-negative) metastatic breast cancer]. 2064 6


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