Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel mono-THF containing synthetic anticancer drug, COBRA-1, was designed for targeting a previously unrecognized unique narrow binding cavity on the surface of alpha-tubulin. COBRA-1 inhibited GTP-induced tubulin polymerization in cell-free tubulin turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Like other microtubule-interfering agents, COBRA-1 activated the proapoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway, as evidenced by rapid induction of c-jun expression.
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PMID:COBRA-1, a rationally-designed epoxy-THF containing compound with potent tubulin depolymerizing activity as a novel anticancer agent. 1086 79

Rac1 is a member of the Ras superfamily of small guanosine triphosphatases (GTPases) that act as molecular switches to control cytoskeletal rearrangements and cell growth. Analogous to Ras, constitutively activating point mutations of Rac1 cause tumorigenic transformation of cell lines. However, there is no information about whether Rac1 is also mutated in vivo. After RT - PCR of Rac1, several clones of seven benign and 10 malignant breast cancer tissues as well as eight breast cancer cell lines were sequenced. Only single-nucleotide polymorphisms of Rac1 could be detected, and none of these corresponded to constitutively activating point mutations that have been used in cell lines for transformation. While sequencing Rac1 in breast tissues, a new Rac1 isoform with an insertion of 19 codons within the reading frame of Rac1 close to switch region II was identified and named Rac1b. The Rac1b protein acts like a fast cycling GTPase in GTP binding and hydrolysis assays. In Northern and Western blot experiments both Rac1 RNA and Rac1 protein had a significantly higher expression in breast cancer tissues compared to normal breast tissue samples. Immunohistochemical staining of Rac1 showed weak Rac1 expression in benign breast disease but high expression level in ductal carcinoma-in-situ, primary breast cancer, and lymph node metastases. In addition, breast tumor cells from patients with recurrent disease had Rac1 expression at the plasma membrane, suggesting activation of Rac1, in patients with aggressive breast cancer. Oncogene (2000).
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PMID:Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. 1087 53

Agents that either promote or inhibit tubulin polymerization exhibit anticancer activity by disrupting normal mitotic spindle assembly and cell division as well as inducing apoptosis. Recently identified novel agents that target tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and COBRA compounds, targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells. Molecular modeling studies predicted a high-affinity interaction of the first COBRA compounds, COBRA-0 and COBRA-1, with a unique hydrophobic binding site on alpha-tubulin located between the GTP/GDP binding site and the M-loop. Further studies showed that COBRA-1 inhibited GTP-induced tubulin polymerization in cell-free tubulin turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. COBRA-1 activated the pro-apoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway. COBRA and SPIKET compounds represent two new classes of tubulin targeting agents that show promise as anticancer drugs.
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PMID:SPIKET and COBRA compounds as novel tubulin modulators with potent anticancer activity. 1124 82

Reaction of sodium N,N-dimethyldithiocarbamate or N,N-diethyldithiocarbamate with arylsulfonyl halides afforded a series of arylsulfonyl-N,N-dialkyl-dithiocarbamates. The reactivity of these new derivatives with cysteine and glutathione has been investigated in order to identify derivatives that might label a cysteine residue of the heterodimeric protein tubulin which plays a critical physiological function in cell division and also possesses enzymatic activity as a GTP-ase. Since many antitumor drugs exert their action by binding to tubulin, inhibiting in this way microtubule association and provoking cell death, some of the most reactive compounds against the thiol reagents found in this work have been assayed for their antitumor activity. Indeed strong tumor cell growth inhibitory properties against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer has been found in vitro for some of the 4-halogeno-, 4-methyl- or 4-carboxyphenyl-substituted arylsulfonyl-N,N-dialkyl-dithiocarbamates. Furthermore, some of these derivative were shown to act as in vitro tubulin polymerization inhibitors using a turbidimetric assay.
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PMID:Arylsulfonyl-N,N-dialkyl-dithiocarbamates as tumor cell growth inhibitors: novel agents targeting beta-tubulin? 1149 35

Agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and monotetrahydrofuran compounds (COBRA compounds), targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization and demonstrated potent cytotoxic activity against cancer cells. COBRA-1 inhibited GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other agents that have shown promise for cancer treatment include phorboxazoles, natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. In standard MTT assays, synthetic phorboxazole A exhibited potent cytotoxicity against NALM-6 acute lymphoblastic leukemia cells (IC50 = 1.7 nM), BT-20 breast cancer cells (IC50 = 3.4 nM), and U373 glioblastoma cells (IC50 = 6.7 nM). Structure-activity studies were reported for seven synthetic analogs of phorboxazole A. Out of these, two showed potent anti-cancer activity. Phorboxazole analog 2 was active against NALM-6 cells (IC50 = 4.8 nM), BT-20 cells (IC50 = 12.6 nM) and U373 cells (IC50 = 27.4 nM), as was analog 3 (NALM-6 IC50 = 5.2 nM, BT-20 IC50 = 11.3 nM, and U373 IC50 = 29.2 nM). Anticancer activity of the phorboxazole analogs was correlated to the presence of certain structural moieties such as portions of the macrolide group, the central oxazole group, and the polyene side chain. The requirement of more than one structural element for activity suggested that at least bimodal interactions of the natural product with key cellular components may occur. Promising anti-mitotic agents with pro-apoptotic activity include inhibitors of the tyrosine kinase BTK. The leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells (IC50 = 17 microM). Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
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PMID:Rationally designed anti-mitotic agents with pro-apoptotic activity. 1156 3

Neurofibromin is a tumor suppressor protein, which is similar in function to the GTPase activating protein (GAP), p120GAP, in that it accelerates inactivation of Ras. Mutations in the NF1 gene cause neurofibromatosis type 1, NF1, an autosomal dominant disease with a diverse spectrum of clinical manifestations, including neurofibromas. Ras activation (GTP binding) is induced by the GTP exchange factor Sos and its inactivation is regulated through the GAPs (p120GAP and neurofibromin). Strikingly, neurofibromin was nearly absent in MB-231 human breast cancer cells and present in the remaining four cell lines studied, with higher levels in BT-474 and MB-453 than in MCF-7 and BT-20 cells, as tested with polyclonal antibodies to both the N-terminal as well as the C-terminal peptides. Coordinated with the near absence of neurofibromin, these cells also presented with much greater levels of P-MAPK and activated Ras. Further, RT-PCR analysis demonstrated the absence of expression of NF1 mRNA type I isoform only in the MB-231 cell lines. This result documents for the first time an altered NF1 expression at the protein and mRNA levels in MDA-MB-231 breast cancer cells.
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PMID:Human breast cancer MDA-MB-231 cells fail to express the neurofibromin protein, lack its type I mRNA isoform and show accumulation of P-MAPK and activated Ras. 1156 91

A human protein termed p21-activated kinase 6 (PAK6), based on homology to the PAK family of serine/threonine kinases, was cloned as an AR interacting protein. PAK6 was a 75-kDa protein with a predicted N-terminal Cdc42/Rac interactive binding domain and a C-terminal kinase domain. PAK6 bound strongly to GTP-Cdc42 and weakly to GTP-Rac. In contrast to most PAKs, kinase activity was not stimulated by Cdc42 or Rac, but could be stimulated by AR binding. PAK6 interacted with the intact AR in a mammalian one-hybrid assay and bound in vitro, without ligand, to the hinge region between the AR DNA- and ligand-binding domains. PAK6 also bound to the ERalpha, and binding was enhanced by 4-hydroxytamoxifen. AR and ERalpha transcriptional activities were inhibited by PAK6 in transient transfections with episomal and integrated reporter genes. AR inhibition was not reversed by transfection with an activated Cdc42 mutant, Cdc42V12, which by itself also inhibited AR transactivation. Epitope-tagged PAK6 was primarily cytoplasmic in the absence or presence of AR and hormone. PAK6 transcripts were expressed most highly in brain and testis, with lower levels in multiple tissues including prostate and breast. PAK6 interaction provides a mechanism for cross-talk between steroid hormone receptors and Cdc42-mediated signal transduction pathways and could contribute to the effects of tamoxifen in breast cancer and in other tissues.
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PMID:AR and ER interaction with a p21-activated kinase (PAK6). 1177 41

Binding of the urokinase-type plasminogen activator (uPA) to its receptor activates diverse cell signaling pathways. How these signals are integrated so that cell physiology is altered remains unclear. In this study, we demonstrated that migration of MCF-7 breast cancer cells and HT-1080 fibrosarcoma cells on serum-coated surfaces is stimulated by agents that activate ERK, including uPA, epidermal growth factor, and constitutively active MEK1. The promigratory activity of these agents was entirely blocked not only by the MEK-specific antagonist PD098059, but also by antagonists of the Rho-Rho kinase pathway, including Y-27632 and dominant-negative RhoA (RhoA-N19). uPA did not significantly increase the level of GTP-bound RhoA, suggesting that the constitutive activity of the Rho-Rho kinase pathway may be sufficient to support ERK-stimulated cell migration. Paradoxically, Y-27632 and RhoA-N19 increased ERK phosphorylation in MCF-7 cells, providing further evidence that ERK activation alone does not promote cell migration when Rho kinase is antagonized. When MCF-7 cell migration was stimulated by ERK-independent processes such as expression of the beta(3) integrin subunit or changing the substratum to type I collagen, Y-27632 and RhoA-N19 failed to inhibit the response. This study supports a model in which the Ras-ERK and Rho-Rho kinase pathways cooperate to promote cell migration. Neutralizing either pathway is sufficient to block the response to agents that stimulate cell migration by activating ERK.
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PMID:Cooperativity between the Ras-ERK and Rho-Rho kinase pathways in urokinase-type plasminogen activator-stimulated cell migration. 1180 8

To identify genes that are involved in breast cancer, suppression subtractive hybridization (SSH) was utilized to construct a breast cancer subtracted library. Differential screening of the library isolated 28 genes which by Northern analysis were highly expressed in the breast cancer cell line MDA-MB-231 compared to the normal breast cell line MCF12A. Sequence analysis revealed that 15 clones coded for previously described genes such as SNAP43, Cyr61, Thymosin beta4, tra1, elongation factor 1alpha, BSF-2/IL6, BiP, and GDP/GTP exchange protein. The remaining 13 clones did not match sequences in GenBank/EMBL database, indicating that they may be novel genes. SNAP43, a subunit of the TBP-TAF complex, was expressed 20-fold higher in MDA-MB-231 compared to MCF12A and several breast cancer cell lines, implying that SNAP43 may be involved in tumorigenesis of a specific subset of breast cancers. Amplification of SNAP43 was not found by Southern analysis. However, genetic alterations of MDA-MB-231 included a deletion of chromosome 14 with a reciprocal translocation t(6;14) and two additional translocations [t(12;14) and t(14;15)] as determined by fluorescent in situ hybridization (FISH) with YAC 823G8 located at chromosome 14q23 which contained SNAP43. Because of the numerous alterations observed by FISH in MDA-MB-231, we further explored the genetic abnormalities in this breast cancer cell line using multiplex FISH (M-FISH) and comparative genomic hybridization (CGH). These cells were replete with numerous complex structural rearrangements and had DNA copy-number imbalances involving multiple chromosomes including gains on chromosomes 2p, 2q31-q32, 3p14-pter, 5q, 6p, 7q36-qter, 11, 14q21-q24, 17p11.2-pter, 17q21-qter, 19, 20, Xp11-q13 and losses on chromosomes 4pter-q32, 8p, 9p21-p24, 10q26-qter, 16p13-pter, 18q12-qter, 22, Xp11.3-p22.1, Xq13-qter. In summary, SSH revealed a number of genes that were either novel or previously not associated with breast cancer. In addition, we found that breast cancer cells abounded with abnormalities as observed by M-FISH and CGH. Together, these results may facilitate defining the genetic alterations associated with breast cancer progression.
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PMID:Discovery of over-expressed genes and genetic alterations in breast cancer cells using a combination of suppression subtractive hybridization, multiplex FISH and comparative genomic hybridization. 1216 92

Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of beta-tubulin and COBRA compounds target a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
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PMID:Structure-based design of novel anticancer agents. 1218 92


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