Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Camptothecin (CPT) is a naturally occurring alkaloid that shows promise in antitumor activity in vitro against various tumor cell lines. Its potential clinical uses, however, are hindered by a lack of reaction selectivity and poor water solubility. Presented herein is a novel polyrotaxane (PR)-based delivery system that could potentially lead to a highly effective yet less toxic CPT therapy. The approach involves the synthesis of the PR-CPT conjugates via hydrolyzable linkages. To enhance the therapeutic efficacy of CPT, a cell-penetrating peptide, LMWP, is linked to the conjugate to allow specific, intratumoral delivery of CPT. To avoid nonselective uptake of the conjugates by normal tissues following administration, the cell-penetrating function of LMWP on the conjugates is masked by heparin binding. This system was designed such that after accumulation at the tumor via the enhanced permeability and retention (EPR) effect, protamine can be subsequently administered to unmask heparin inhibition on LMWP, permitting intracellular uptake of the LMWP-PR-CPT conjugates. Once inside the tumor, CPT molecules are detached from the PR chain by hydrolysis, yielding a sustained concentration of CPT within tumor cells. In this paper, we demonstrated the in vitro feasibility of this delivery system. The LMWP-PR-CPT conjugates yielded a sevenfold increase in the overall CPT solubility, as well as a sustained release of CPT over a period of more than 7 days. Intracellular uptake of these conjugates by A2780 human ovarian cancer cells and regulation of such uptake by heparin and protamine were tested by MTT assay and confocal/flow cytometric methods, respectively.
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PMID:A novel polyrotaxane-based intracellular delivery system for camptothecin: in vitro feasibility evaluation. 1760 67

D-allose, an aldo-hexose, is a rare sugar whose biological functions remain largely unclear. Recently, we demonstrated a novel inhibitory effect of D-allose on production of reactive oxygen species (ROS). Here, we focused on investigating cryoprotective effects of D-allose on cell viability. Mammalian cell lines including OVCAR-3 (human ovarian cancer), HeLa (human cervical cancer), HaCaT (human skin keratinocytes), HDF (human dermal fibroblasts) and NIH3T3 (murine fibroblasts) cells were frozen at -80 degrees C in culture media with various D-allose concentrations. Cells were allowed to recover for 24 h, 1 week or 1 month prior to survival assessment using the trypan blue dye exclusion test, when cell proliferation was evaluated by MTT assay. A beneficial protective role of D-allose on cell survival was found, similar to that of trehalose (disaccharide of glucose), a recognized cryoprotectant. The results suggest that D-allose as a sole additive may provide effective protection for mammalian cells during freezing. Practical studies now need to be performed with D-allose, for example to determine optimal freezing protocols and explore potential for preservation of tissues or organs at non-freezing temperatures.
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PMID:Cryoprotective effects of D-allose on mammalian cells. 1764 76

In the development of anti-cancer drugs, it is important to yield selective cytotoxicity primarily against tumor tissues. To achieve this goal, the use of a polymer-drug conjugate appears to be appealing, simply because it can take the advantage of the so-called enhanced permeability and retention (EPR) effect due to vascular leak in tumors. Among various types of polymers, polyrotaxane (PR) is an interesting candidate and warrants further consideration. It is a self-assembled polymer made entirely of biocompatible components, by threading alpha-cyclodextrin (alpha-CD) molecules with the poly(ethylene glycol) (PEG) chain. The abundance in functional -OH groups on the CD residues renders PR the capability of carrying a large dose of small anti-tumor agents for delivery. Herein, we presented a novel PR-based delivery system using doxorubicin (DOX) as the model anti-cancer drug. Daunorubicin (DNR) was conjugated to the PR polymer via hydrolysable linkages, and upon hydrolysis, doxorubicin was released as the cytotoxic drug. To facilitate an intracellular uptake by the tumor cells of the PR-DOX conjugates, a cell-penetrating low molecular weight protamine (LMWP) peptide was further attached to the two termini of the PR chain. Using an innovative principle established in our laboratory, such as via the inhibition of the cell-penetrating activity by binding with heparin and reversal of this inhibition by subsequent addition of protamine, cellular uptake of the polymer-drug conjugates could be readily regulated. In this paper, we performed in vitro studies to demonstrate the feasibility of this delivery system. The LMWP-PR-DOX conjugates, which yielded a sustained release of DOX over a period of greater than 4 days, were successfully synthesized. Intracellular uptake of these conjugates by A2780 human ovarian cancer cells and regulation of such uptake by heparin and protamine were confirmed by using the MTT assay and also the confocal microscopy method.
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PMID:In vitro assessment of a novel polyrotaxane-based drug delivery system integrated with a cell-penetrating peptide. 1790 80

Peripheral benzodiazepine receptor (PBR), a mitochondrial protein involved in cell proliferation and differentiation, and carbonic anhydrase IX (CA IX), an intrinsic marker of hypoxia, have been studied in the panel of human breast (MCF-7, BT- 20, MDA-MB-453, MDA-MB-231) and ovarian (A2780, A2780/CP, A2780/ADR, CH1, SKOV-3) carcinoma cell lines that differ by malignant progression. The expression of both antigens was detected by staining with the PBR-specific 8D7 and CA IX-specific M75 monoclonal antibodies and quantitated by flow cytometry. PBR was related to mitochondrial mass and CA IX to the cell density. Breast carcinoma cell lines showed higher relative fluorescence intensity of PBR expression than ovarian cell lines, with the exception of A2780/CP cisplatin-resistant subline that was comparable to highly invasive MDA-MB-231 breast line. Among the breast cell lines, PBR expression increased with their invasive potential. The ovarian cell lines showed greater variability in fluorescence intensities and the expression of PBR did not correlate with the amount of mitochondria. Mitochondrial PBR density disclosed significant difference between cisplatin-sensitive (low PBR density) and -resistant (high PBR density) ovarian cell lines. MTT test showed higher sensitivity of 2 breast cell lines MCF-7 and MDA-MB-231 (IC50 < 75 microM) to PBR ligand PK 11195 than all examined ovarian cell lines (IC50 > 90 microM, in chemo- and radio- resistant lines IC50 > 110 microM). Growth inhibitory effect of PK 11195 did not correlate with the amount of PBR and was mediated probably by another, PBRindependent mechanisms. The expression of CA IX was only marginal in majority of tested cell lines in subconfluent conditions and was inducible by high cell density. More than 5% of positive cells in sparse culture have been found in MDA-MB-231 and MDA-MB-453 breast cell lines while more than 15% of A2780/ADR adriamycin-resistant ovarian cells were positive for CA IX expression under the same conditions. Our data indicate that PBR expression in breast and ovarian carcinoma cell lines is not proportional to the amount of mitochondria and should be expressed relatively to the cell mitochondrial mass. This assessment allows establishing high PBR density as a measure of aggressiveness (invasion in breast and resistance in ovarian cancer). Observation of relatively high CA IX expression in A2780/ADR cells evokes the assumption that multidrug resistance might be connected with selection advantage towards CA IX expressing cells.
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PMID:Expression of new prognostic markers, peripheral-type benzodiazepine receptor and carbonic anhydrase IX, in human breast and ovarian carcinoma cell lines. 1794 39

Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC(50)=0.35 muM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiation-induced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4',6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gammaH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.
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PMID:Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo. 1807 53

The reversing effect of wild-type PTEN gene on resistance of C13K cells to cisplatin and its inhibitory effect on the phosphorylation of protein kinase B (AKT) were studied. The expression of PTEN mRNA and protein in OV2008 cells and C13K cells were semi-quantitatively detected by using RT-PCR and Western blotting. Recombinant eukaryotic expression plasmid containing human wild-type PTEN gene was transfected into C13K cells by lipofectamine2000. The expression of PTEN mRNA was monitored by RT-PCR and the expression of PTEN, Akt, p-Akt protein were analyzed by Western blotting in PTEN-transfected and non-transfected C13K cells. Proliferation and chemosensitivity of cells to DDP were measured by MTT, and cell apoptosis was detected by flow cytometry after treatment with cisplatin. The expression of PTEN mRNA and protein in OV2008 cells were significantly higher than those in C13K cells. After transfection with PTEN gene for 48 h, the expression of PTEN mRNA and protein in C13K cells were 2.04 +/- 0.10, 0.94 +/- 0.04 respectively and the expression of p-Akt protein (0.94 +/- 0.07) was lower than those in control groups (1.68 +/- 0.14, 1.66 +/- 0.10) (P < 0.05). The IC(50) of DDP to C13K cells transfected with PTEN (7.2 +/- 0.3 micromol/L) was obviously lower than those of empty-vector transfected cells and non-transfected cells (12.7 +/- 0.4 micromol/l, 13.0 +/- 0.3 micromol/L) (P<0.05). The apopototis ratio of wild-type PTEN-transfected, empty vector transfected and non-transfected C13K cells were (41.65 +/- 0.87)%, (18.61 +/- 0.70)% and (15.28 +/- 0.80)% respectively, and the difference was statistically significant (P<0.05). PTEN gene plays an important role in ovarian cancer multidrug resistance. Transfection of PTEN could increase the expression of PTEN and restore drug sensitivity to cisplatin in human ovarian cancer cell line C13K with multidrug-resistance by decreasing the expression of p-Akt.
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PMID:Reversal of multidrug resistance and inhibition of phosphorylation of AKT in human ovarian cancer cell line by wild-type PTEN gene. 1823 51

To investigate the relationship between MDR1 and MDR3 gene and drug resistance to cisplatin of ovarian cancer cells. Two siRNAs (MDR1, MDR3) which specifically targeted MDR1 and MDR3 genes were transferred into A2780/DDP cells. Then double staining with Annexin-V-FITC/PI was used to detect cell apoptosis by the flow cytometry (FCM). A2780/DDP cell viability was determined by MTT. MDR1 and MDR3 mRNA were assessed by RT-PCR. Caspase-3 protein was detected by Western blotting. Transfection of MDR1 and MDR3 siRNA into A2780/DDP cells failed to reverse the drug-resistance of A2780/DDP cells to cisplatin (P>0.05). No significant difference in the apoptosis efficiency was observed between the MDR1 and MDR3 siRNA, pSuppressorNeo vector transfection cells and untreated cells (P>0.05). In the presence of cisplatin of different concentrations, the viability of A2780/DDP cells was not significantly decreased after the transfection. No changes in MDR1 and MDR3 mRNA were found in MDR1 and MDR3 siRNA-transfected A2780/DDP cells. As compared with pSuppressorNeo and untreated groups, no significant difference existed in the expression of MDR1 and MDR3 mRNA (P>0.05). The expression of caspase-3 protein in MDR1 and MDR3 siRNA transfected A2780/DDP cells was not significantly increased. It is concluded that multidrug resistance induced by cisplatin in ovarian carcinoma cell lines is not due to overexpression of MDR1 and MDR3 gene. The drug resistance of ovarian carcinoma cells to cisplatin is not mediated by P-glycoprotein.
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PMID:MDR1 and MDR3 genes and drug resistance to cisplatin of ovarian cancer cells. 1823 53

We have reported the synthesis and biological evaluation of a decavanadate Na(4)Co(H(2)O)(6)V(10)O(28).18H(2)O (CoV(10)) designed as a potential antitumoral agent. The human cancer cell lines SMMC-7721 (liver cancer) and SK-OV-3 (ovary cancer) were tested for their viability by the MTT method in vitro, which showed that the compound exhibited a remarkable activity against two cell lines with IC(50) values smaller than 0.24 microg/mL, 0.32 microg/mL, respectively. CoV(10) showed the tumor growth suppression for Hep-A-22 (mice liver cancer) in tumor bearing mice in vivo. In addition, using flow cytometry analysis, the ratio of apoptotic cells was up to 8.33% with treatment of CoV(10) at 1.56 microg/mL after 30 min, suggesting that the antitumoral activity of CoV(10) comes from the activation of the apoptotic pathway.
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PMID:Synthesis and biological evaluation of decavanadate Na4Co(H2O)6V10O28.18H2O. 1837 19

Doxorubicin is an effective anthracycline used for cancer therapy. However, the clinical application of doxorubicin has been largely limited by its irreversible cardiotoxicity, which is mainly induced by the primary amine group. In this study, we structurally modified doxorubicin by converting the primary amine into an acid-labile amide before assessing the acute cardiac effect of doxorubicin (pristine or modified) on cardiomyocyte contractile function. Contractile properties of murine cardiomyocytes were analyzed including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and maximal velocity of shortening/re-lengthening (+/-dL/dt). Cell toxicity and survival rate were evaluated using the MTT assay. The doxorubicin-free base was amidized by reacting with 3,4,5,6-tetrahydophthalic anhydride (THPA) or 3,3,4,4-tetramethylsuccinic anhydride (TMSA) to yield doxorubicin-THPA or -TMSA. Acute exposure of pristine doxorubicin (10(-9)-10(-5)M) for 30 min significantly prolonged TPS and TR(90) without affecting PS and +/-dL/dt. Interestingly, doxorubicin-induced prolongation of TPS and TR(90) was significantly attenuated or abrogated by amidization of doxorubicin. Neither doxorubicin-THPA nor -TMSA affected PS and +/-dL/dt. ROS and MTT assay revealed significantly reduced ROS production and cardiac cell toxicity from amidized doxorubicin compared with the pristine compound. Comparable cytotoxicity in human ovarian cancer SKOV-3 cells was observed between amidized and pristine doxorubicin compounds. These data provide evidence for the first time that structural modification of doxorubicin alleviates its cardiac toxicity.
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PMID:Amidization of doxorubicin alleviates doxorubicin-induced contractile dysfunction and reduced survival in murine cardiomyocytes. 1846 42

Four new oleanane-type triterpene saponins, xanifolia-Y0 (1), xanifolia-Y2 (2), xanifolia-Y3 (3), and xanifolia-Y7 (4), were isolated from the husks of Xanthoceras sorbifolia along with two known analogues, xanifolia-Y8 (5) and xanifolia-Y10 (6). The structures of 1-4 were determined by spectroscopic data interpretation and chemical degradation. Compounds 1-6 were evaluated for their cell-growth inhibition activity toward human ovarian cancer cells (OVCAR3) by a MTT assay, and the IC50 values ranged from 4 to 13 microM. On the basis of the results obtained, it is concluded that a C-3 trisaccharide with a galactose and acylation with an angeloyl group at both C-21 and C-22 are important for cell inhibition activity for this class of compounds.
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PMID:Cytotoxic acylated triterpene saponins from the husks of Xanthoceras sorbifolia. 1854 75


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