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: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two compounds having a camptothecin (CPT) analog conjugated to the 4beta-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1[camptothecin-(para)-4beta-amino-4'-O-demethylepipodophyllotoxin] had no activity against topoisomerase II (TOP II), but inhibited topoisomerase I (TOP I) with an IC(50) value 2-fold higher than CPT. W2 [camptothecin-(ortho)-4beta-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC(50) values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity against the KB cell line, although the protein-linked DNA breaks (PLDBs) generated by W2 in KB cells were about 4-fold more than those of W1. No cross-resistance with the two conjugates was seen in a VP-16-resistant KB subline, which showed down-regulation of TOP II and overexpression of the multiple drug resistance-associated protein, or in a vincristine-resistant KB subline with overexpression of gp-170/mdr-1. The CPT-resistant KB variant (KB CPT 100), which has a reduction in TOP I content and another mechanism that occurs post-PLDB formation, was partially resistant to both compounds. W1 was not affected by this post-PLDB resistance mechanism. Cell cycle analysis demonstrated that W1 and W1 had similar cell cycle effects on KB and KB CPT 100 cells, which accumulated in S-phase upon drug treatment. These results suggested that W1 and W2 exerted their cytotoxicity through TOP I. In CPT-resistant cells, however, an unidentified target also may be involved in the cytotoxic action of W1 and TOP II may still be a target for W1. In vivo, W1 was more effective against the growth of human prostate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor activity and unique biochemical mechanism of action, W1 warrants exploration as an antitumor compound.
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PMID:Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4beta-amino-4'-O-demethylepipodophyllotoxin conjugates. 1066 Jan 16

KAI1 is a metastasis suppressor gene which is capable of inhibiting the processes of tumor metastasis without affecting tumorigenicity per se. We found that etoposide, a topoisomerase II inhibitor, is able to activate the expression of the KAI1 gene in a dose-dependent manner in human prostate cancer cell lines, ALVA, DU145, and PC-3 as well as in human lung carcinoma cell A549. The activation of the KAI1 gene was mainly mediated by the c-Jun gene in the PC-3 and DU145 cell lines, while it was mediated by both p53 and c-Jun genes in the A549 cell line. These results suggest that the augmentation of the KAI1 gene expression is independently controlled by p53 and c-Jun at the transcriptional level in the human cancer cell lines. Furthermore, treatment of these cell lines with etoposide resulted in significant reduction of cellular invasion measured by the Matrigel invasion chamber. Because etoposide has been shown to be effective on advanced prostate cancer when used in combination with other regimens, our results provide further rationale to use this drug as an antimetastatic agent.
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PMID:Activation of the tumor metastasis suppressor gene, KAI1, by etoposide is mediated by p53 and c-Jun genes. 1091 45

Chemoprevention of prostate cancer is the administration of agents to prevent, inhibit, or delay progression of prostate cancer. Asian men have a much lower incidence of prostate cancer than men in Europe or the USA. Asian food includes low-fat, high-fiber diets, which provide a rich supply of weak dietary estrogens. These estrogens have been proposed as chemopreventive agents. In addition to their estrogenic activity, many of these plant compounds can interfere with steroid metabolism and bioavailability and can also inhibit enzymes, such as tyrosine kinase or topoisomerase, which are important for cellular proliferation. In addition, nutritional factors such as reduced fat intake, vitamin E, vitamin D, and selenium may have a protective effect against prostate cancer. The fact was proven in large epidemiological studies as well as experimental observations. In the animal model, the progression of established tumors can be inhibited by these agents. A number of studies to investigate the effect of possible chemopreventive agents for men at high risk of prostate cancer are established. End points for evaluation are mainly based on changes in PSA, changes of histological precursors, or time of onset of clinical disease. The concept of chemoprevention in prostate cancer might have a significant impact on the incidence and mortality of this disease.
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PMID:[Chemoprevention of prostatic carcinoma]. 1095 70

Insulin-like growth factor-binding proteins (IGFBPs) both stimulate and inhibit IGF activity, and in the M12 prostate cancer cell line, overexpression of IGFBP-4 was shown to delay tumorigenesis while decreasing the production of IGFBP-2. We have performed the reverse experiment, inhibition of IGFBP-4 expression with antisense complementary DNA, in two prostate tumor cell lines, ALVA-31 and M12. Expression of antisense messenger RNA transcripts was verified by RNase protection assays, and inhibition of mature IGFBP-4 in cell medium was demonstrated by Western blotting. Both transfected lines (ALVA-31asBP4 and M12asBP4) proliferated more slowly in monolayer culture than parental controls. Colony formation in soft agar was strongly inhibited in both cases, and the rate of tumor formation and growth in male athymic nude mice injected with M12asBP4 was markedly reduced relative to that in mice receiving M12 control cells. Apoptosis induced by the topoisomerase inhibitor etoposide was also enhanced in transfected cells. The effects on colony formation in soft agar and tumor formation in mice were maintained for the duration of the experiments, in contrast to the delayed growth observed in the previous study of IGFBP-4 overexpression. A significant difference was found in the patterns of IGFBP expression; production of both messenger RNA and protein for IGFBP-3 and IGFBP-6 was greatly increased in the M12asBP4 and ALVA31asBP4 cell lines. Up-regulation of these binding proteins has been observed in association with actions of 1,25-dihydroxyvitamin D(3) in prostate cancer cells, and the data suggest a role for IGFBP-3 and IGFBP-6 in the suppression of prostate tumor cell growth.
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PMID:Inhibition of growth and increased expression of insulin-like growth factor-binding protein-3 (IGFBP-3) and -6 in prostate cancer cells stably transfected with antisense IGFBP-4 complementary deoxyribonucleic acid. 1131 65

The extent of chromosomal rearrangements correlates positively with the level of expression of the nuclear matrix high mobility group (HMG) proteins HMGI(Y) when tested in three human prostate cancer cell lines (PC-3 > DU-145 > LNCaP). HMGI(Y), topoisomerase II, and A-T-rich sequences have been reported to be located at the base of the DNA loop domains in both the nucleus and chromosome and are juxtapositioned for chromosomal rearrangement. Transfecting and expressing full-length HMG-I into the LNCaP cell markedly enhanced the presence and heterogeneity of unbalanced (nonreciprocal) chromosomal rearrangements but not of balanced rearrangements. Unbalanced chromosomal rearrangements are common in solid human tumors.
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PMID:High mobility group protein I(Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells. 1183 May 13

The pyrazoloacridone, KW-2170, an alkylating agent and topoisomerase II inhibitor, is being developed by Kyowa Hakko Kogyo as a potential treatment for cancer [273964], [409111], [422561]. By December 2001, KW-2170 had entered phase II trials in the US, following approval for the trial from the FDA, which was received in November 2001. At this time, the company planned to extend the phase II trials to Australia, Singapore, Taiwan and Costa Rica using data from US phase I trials. Accelerated Japanese trials were also planned, and an NDA was anticipated for 2006, with non-small-cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer and breast cancer as the targets [434794], [444539]. By August 2002, Japanese phase I trials had been completed [460177].
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PMID:KW-2170 (Kyowa Hakko Kogyo). 1280 63

We report the identification and characterization of a novel potent inhibitor of DNA topoisomerase I: lamellarin D (LAM-D), initially isolated from a marine mollusk, Lamellaria sp., and subsequently identified from various ascidians. This alkaloid, which displays potent cytotoxic activities against multidrug-resistant tumor cell lines and is highly cytotoxic to prostate cancer cells, bears a 6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-one pentacyclic planar chromophore, whereas its synthetic 5,6-dehydro analogue, LAM-501, has a significantly tilted structure. DNA binding measurements by absorbance, fluorescence, and electric linear dichroism spectroscopy show that LAM-D is a weak DNA binder that intercalates between bp of the double helix. In contrast, the nonplanar analogue LAM-501 did not bind to DNA and failed to inhibit topoisomerase I. DNA intercalation may be required for the stabilization of topoisomerase I-DNA complexes by LAM-D. In the DNA relaxation assay, LAM-D strongly promoted the conversion of supercoiled DNA into nicked DNA in the presence of topoisomerase I. The marine product was approximately 5 times less efficient than camptothecin (CPT) at stabilizing topoisomerase I-DNA complexes, but interestingly, the two drugs exhibited slightly distinct sequence specificity profiles. Topoisomerase I-mediated DNA cleavage in the presence of LAM-D occurred at some sites common to CPT, but a few specific sites identified with CPT but not with LAM-D or conversely unique sites cleaved by LAM-D but not by CPT were detected. The distinct specificity profiles suggest that LAM-D and CPT interact differently with the topoisomerase I-DNA interface. A molecular modeling analysis provided structural information on the orientation of LAM-D within the topoisomerase I-DNA covalent complex. The marine alkaloid did not induce DNA cleavage by topoisomerase II. Immunoblotting experiments revealed that endogenous topoisomerase I was efficiently trapped on DNA by LAM-D in P388 and CEM leukemia cells. P388/CPT5 and CEM/C2 cell lines, both resistant to CPT and expressing a mutated top1 gene, were cross-resistant to LAM-D. Collectively, the results identify LAM-D as a novel lead candidate for the development of topoisomerase I-targeted antitumor agents.
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PMID:Lamellarin D: a novel potent inhibitor of topoisomerase I. 1461 38

The hereditary prostate cancer 1 (HPC1) allele maps to the RNASEL gene encoding a protein (RNase L) implicated in the antiviral activity of interferons. To investigate the possible role of RNase L in apoptosis of prostate cancer cells, we decreased levels of RNase L by severalfold in the DU145 human prostate cancer cell line through the stable expression of a small interfering RNA (siRNA). Control cells expressed siRNA with three mismatched nucleotides to the RNase L sequence. Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A). Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)]. In contrast, cells expressing siRNA to the RNase L inhibitor RLI (HP68) showed enhanced apoptosis in response to Topo I inhibitor alone or in combination with TRAIL. An inhibitor of c-Jun NH(2)-terminal kinases reduced apoptosis induced by treatment with either 2-5A or the combination of camptothecin and TRAIL, thus implicating c-Jun NH(2)-terminal kinase in the apoptotic signaling pathway. Furthermore, prostate cancer cells were sensitive to apoptosis from the combination of 2-5A with either TRAIL or Topo I inhibitor, whereas normal prostate epithelial cells were partially resistant to apoptosis. These findings indicate that RNase L integrates and amplifies apoptotic signals generated during treatment of prostate cancer cells with 2-5A, Topo I inhibitors, and TRAIL.
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PMID:HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. 1560 85

The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase IIalpha inhibitor). We investigated the role of nuclear factor kappa B (NF-kappaB) signaling in HGF/SF-mediated protection of human prostate cancer (DU-145) and Madin-Darby canine kidney (MDCK) epithelial cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-kappaB associated with the transient loss of the inhibitory subunit IkappaB-alpha. Exposure to HGF/SF caused the activation of an NF-kappaB luciferase reporter that was blocked or attenuated by the expression of a mutant 'super-repressor' IkappaB-alpha. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-kappaB family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-kappaB-binding oligonucleotides. The HGF/SF-mediated protection of DU-145 and MDCK cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IkappaB-alpha super-repressor. The ability of HGF/SF to activate NF-kappaB signaling was dependent on c-Akt --> Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3'-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-kappaB, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-kappaB activity. HGF/SF induced the expression of several known NF-kappaB target genes (cIAP-1 (cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-kappaB-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-kappaB through a c-Akt --> Pak1 signaling pathway that is also dependent on Src, and that NF-kappaB contributes to HGF/SF-mediated protection against ADR.
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PMID:Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. 1568 34

Lamellarin D (LAM-D) is a marine alkaloid endowed with potent cytotoxic activities against various tumor cells, in particular human prostate cancer cells and leukemia cells. Its cytotoxic action is dependent, at least in part, to its capacity to inhibit topoisomerase I. P388CPT5 murine leukemia cells resistant to the reference topoisomerase I poison camptothecin (CPT) are cross-resistant to LAM-D but the relative resistance index (RRI) is significantly reduced with LAM-D (RRI=21) compared to CPT (RRI=103). To comprehend further the mechanism of action of this novel marine antitumor agent, we have investigated the influence of the P glycoprotein (Pgp) on the cytotoxicity of LAM-D and the proapoptotic effects induced by the alkaloid. P388CPT5 cells, expressing a mutated top1 gene, display a functional Pgp, as judged from cytometry experiments performed with cells treated with rhodamine 123 or calcein-ester whereas no Pgp activity was detected with the parental P388 cells. P388CPT5 cells are also cross-resistant to the topoisomerase II poisons doxorubicin and etoposide but the resistance is abolished in the presence of verapamil or quinine (at non toxic concentrations) which reverse the multidrug resistance (MDR) phenotype. In contrast, the RRI measured with LAM-D and CPT remain unchanged in the presence of the two MDR reversal agents. The effects of LAM-D on the cell cycle progression were different in the parental P388 cells compared with the CPT-resistant which were blocked in the S and subsequently G2-M phases of the cell cycle. Cytometry experiments with the JC-1 fluorescent marker revealed that LAM-D and CPT promoted apoptosis in parental P388 cells via an activation of the mitochondrial pathway. In contrast, a massive depolarisation of the mitochondrial membrane potential and a nuclear fragmentation were detected only with LAM-D on P388CPT5 cells. This in vitro work identifies LAM-D as a potent pro-apoptotic agent and its cytotoxic action is fully maintained in multidrug-resistant cells compared to the sensitive parental cell line.
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PMID:Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux. 1580 2


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