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1.  MMP-9 Inhibition Downregulates Radiation-induced NF-κ Activity Leading to Apoptosis in Breast Tumors 
Purpose
Novel strategies are needed to prevent the high mortality rates of several types of cancer. These high rates stem from tumor resistance to radiation therapy, which is thought to result from the induction of matrix metalloproteinases and plasminogen activators. In the present study, we show that the modulation of MMP-9 expression, using adenoviral-mediated transfer of the antisense MMP-9 gene (Ad-MMP-9), affects breast cancer sensitivity to radiation.
Experimental Design
In the present study, we used antisense MMP-9 adenoviral construct (Ad-MMP-9) to downregulate the expression of MMP-9 in MDA MB 231 breast cancer cell lines in vitro prior to irradiation and subsequently incubated cells in hypoxic condition. In vivo studies were performed with orthotopic breast tumors and the radiosensitivity evaluated both in vitro and in vivo.
Results
Ad-MMP-9 infection resulted in downregulation of radiation-induced levels of hypoxia-inducible factor 1 alpha (HIF1α) and MMP-9 under hypoxic conditions in MDA MB 231 breast cancer cells. In addition, Ad-MMP-9 in combination with radiation decreased levels of the transcription factors NF-κB and AP 1, both of which contribute to the radioresistance of breast tumors. Finally, the triggering of the Fas-Fas-L apoptotic cascade, which resulted in the cleavage of PARP-1 and caspases 10, 3 and 7, signifies the efficiency of combined treatment of Ad-MMP-9 and radiation. Treatment with Ad-MMP-9 plus radiation completely regressed tumor growth in orthotopic breast cancer model.
Conclusions
In summary, integrating gene therapy (adenovirus-mediated inhibition of MMP-9) with radiotherapy could have a synergistic effect, thereby improving the survival of patients with breast cancer.
doi:10.1158/1078-0432.CCR-07-2060
PMCID: PMC2410036  PMID: 18519796
Ad-MMP-9; Radiation; Orthotopic breast tumor; Hypoxia; Tumor growth
2.  In vitro Evaluation of Eclipta alba against Serogroups of Leptospira interrogans 
Leptospirosis is now acknowledged as the most widespread zoonoses in the world. Hundreds of cases occur in India every year accounting for considerable morbidity and sizable mortality. Several studies have delineated the epidemiology, pathology and variable clinical features of this condition. The present study comprises the importance and utilization of traditional based medicines to overcome the adverse reaction by conventional drugs and standardize the technology. The antileptospiral activity of Eclipta alba L. was well studied by both tube dilution and micro dilution techniques and the result showed better inhibitory action against various serogroups of Leptospira interrogans. L. australis, L. autumnalis and L. grippotyphosa are inhibited by both water and ethanol extract by tube dilution technique. The MIC level observed are 50 μg and 100 μg respectively. Similarly acetone extract, Icterohaemorrhagiae was responded to 200 μg/ml as MIC whereas in petroleum ether extract, no inhibition was observed. In the case of micro dilution technique, the entire inhibition rates are supported to the tube dilution technique. It showed that the micro dilution technique is the best method where we obtained the results within 30 minutes; at the same time tube dilution technique takes minimum of 7 days to provide the result.
doi:10.4103/0250-474X.49124
PMCID: PMC3040876  PMID: 21369443
Leptospirosis; Leptospira interrogans; Eclipta alba L.; tube dilution; micro dilution
3.  Inhibition of invasion, angiogenesis, tumor growth and metastasis by adenovirus-mediated transfer of antisense uPAR and MMP-9 in non-small cell lung cancer cells 
Molecular cancer therapeutics  2005;4(9):1399-1408.
Lung cancer is currently the leading cause of cancer deaths in this country. Conventional therapeutic treatments including surgery, chemotherapy and radiation therapy, have achieved only limited success. The overexpression of proteases such as urokinase-type plasminogen activator (uPA), its receptor (uPAR) and matrix metalloproteinases (MMPs), is correlated with the progression of lung cancer. In the present study, we used a replication-deficient adenovirus capable of expressing antisense uPAR and antisense MMP-9 transcripts to simultaneously downregulate uPAR and MMP-9 in H1299 cells. Ad-uPAR-MMP-9 infection of H1299 cells resulted in a dose-and time-dependent decrease of uPAR protein levels and MMP-9 activity as determined by western blotting and gelatin zymography respectively. Corresponding immunohistochemical analysis also demonstrated that Ad-uPAR-MMP-9 infection inhibited uPAR and MMP-9 expression. As shown by Boyden chamber assay, Ad-uPAR-MMP-9 infection significantly decreased the invasive capacity of H1299 cells compared to mock and Ad-CMV (empty vector)-infected cells in vitro. Furthermore, Ad-uPAR-MMP-9 infection inhibited capillary-like structure formation in H1299 cells co-cultured with endothelial cells in a dose-dependent manner compared with mock- and Ad-CMV-infected cells. Ad-uPAR-MMP-9 injection caused the regression of subcutaneously induced tumors after subcutaneous injection with H1299 lung cancer cells and inhibited lung metastasis in the metastatic model with A549 cells. These data suggest that Ad-uPAR-MMP-9 demonstrates its antitumor activity against both established and early phases of lung cancer metastases by causing the destruction of the tumor vasculature. In summary, adenovirus-mediated inhibition of uPA-uPAR interaction and MMP-9 on the cell surface may be a promising anti-invasion and anti-metastasis strategy for cancer gene therapy.
doi:10.1158/1535-7163.MCT-05-0082
PMCID: PMC1343495  PMID: 16170032
lung; invasion; MMP-9; uPAR; antisense; angiogenesis; uPA (urokinase-type plasminogen activator); uPAR (uPA receptor); CMV (cytomegalovirus); SV40 (simian virus type 40); PBS (phosphate-buffered saline); MMP-9 (matrix metalloprotease-9); metastasis

Results 1-3 (3)