Department of Animal Biology

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Browsing Department of Animal Biology by Author "Agarwal, Smita"
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    Celecoxib inhibits MDR1 expression through COX-2-dependent mechanism in human hepatocellular carcinoma (HepG2) cell line
    ( 2010-04-01) Roy, Karnati R. ; Reddy, Gorla V. ; Maitreyi, Leela ; Agarwal, Smita ; Achari, Chandrani ; Vali, Shireen ; Reddanna, Pallu
    The role of COX-2 in the regulation of the expression of MDR1, a P-glycoprotein involved in hepatocellular carcinoma cell line, HepG2, was studied in the present investigation. Celecoxib, a selective inhibitor of COX-2, at 25 μM concentration increased the accumulation of doxorubicin in HepG2 cells and enhanced the sensitivity of the cells to doxorubicin by tenfold. The induction of MDR1 expression by PGE2 and its downregulation by celecoxib or by COX-2 knockdown suggests that the enhanced sensitivity of HepG2 cells to doxorubicin by celecoxib is mediated by the downregulation of MDR1 expression, through COX-2-dependent mechanism. Further studies revealed the involvement of AP-1 in the celecoxib-induced downregulation of MDR1 expression. These experimental studies correlated well with in silico predictions and further suggested the inactivation of the signal transduction pathways involving ERK, JNK and p38. The present study thus demonstrates the usefulness of COX-2 intervention in overcoming the drug resistance in HepG2 cells. © 2009 Springer-Verlag.
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    Celecoxib inhibits MDR1 expression through COX-2-dependent mechanism in human hepatocellular carcinoma (HepG2) cell line
    ( 2010-04-01) Roy, Karnati R. ; Reddy, Gorla V. ; Maitreyi, Leela ; Agarwal, Smita ; Achari, Chandrani ; Vali, Shireen ; Reddanna, Pallu
    The role of COX-2 in the regulation of the expression of MDR1, a P-glycoprotein involved in hepatocellular carcinoma cell line, HepG2, was studied in the present investigation. Celecoxib, a selective inhibitor of COX-2, at 25 μM concentration increased the accumulation of doxorubicin in HepG2 cells and enhanced the sensitivity of the cells to doxorubicin by tenfold. The induction of MDR1 expression by PGE2 and its downregulation by celecoxib or by COX-2 knockdown suggests that the enhanced sensitivity of HepG2 cells to doxorubicin by celecoxib is mediated by the downregulation of MDR1 expression, through COX-2-dependent mechanism. Further studies revealed the involvement of AP-1 in the celecoxib-induced downregulation of MDR1 expression. These experimental studies correlated well with in silico predictions and further suggested the inactivation of the signal transduction pathways involving ERK, JNK and p38. The present study thus demonstrates the usefulness of COX-2 intervention in overcoming the drug resistance in HepG2 cells. © 2009 Springer-Verlag.
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    Eicosanoids in inflammation and cancer: The role of COX-2
    ( 2009-12-01) Agarwal, Smita ; Reddy, Gorla Venkateswara ; Reddanna, Pallu
    Eicosanoids, a family of oxygenated metabolites of eicosapolyenoic fatty acids, such as arachidonic acid, formed via the lipoxygenase, cyclooxygenase (COX) and epoxygenase pathways, play an important role in the regulation of various pathophysiological processes, including inflammation and cancer. COX-2, the inducible isoform of COX, has emerged as the key enzyme regulating inflammation, and promises to play a considerable role in cancer. Although NSAIDs have been in use for centuries, the COX-2 selective inhibitors - coxibs - have emerged as potent anti-inflammatory drugs with fewer gastric side effects. As COX-2 plays a major role in neoplastic transformation and cancer growth, by downregulating apoptosis and promoting angiogenesis, invasion and metastasis, coxibs have a potential role in the prevention and treatment of cancer. Recent studies indicate their possible application in overcoming drug resistance by downregulating the expression of MDR-1. However, the cardiac side effects of some of the coxibs have limited their application in treating various inflammatory disorders and warrant the development of COX-2 inhibitors without side effects. This review will focus on the role of COX-2 in inflammation and cancer, with an emphasis on novel approaches to the development of COX-2 inhibitors without side effects. © 2009 Expert Reviews Ltd.
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    Inhibition of 12-LOX and COX-2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K-Akt signalling pathways
    ( 2009-11-01) Agarwal, Smita ; Achari, Chandrani ; Praveen, D. ; Roy, Karnati R. ; Reddy, Gorla Venkateswara ; Reddanna, Pallu
    Eicosanoids, the oxygenated metabolites of arachidonic acid (AA), mediate a variety of human diseases, such as cancer, inflammation and arthritis. To evaluate the role of eicosanoids in epidermoid carcinoma, the expression of AA metabolizing enzymes, such as lipoxygenases (LOXs) and cyclooxygenases (COXs), was analysed in a human epidermoid carcinoma cell line (A431). These studies revealed overexpression of 12-R-LOX and COX-2 in A431 cells. Baicalein (a 12-LOX inhibitor) and celecoxib (a COX-2 inhibitor) significantly reduced thymidine incorporation, whereas 12-(R)-HETE and 12-(S)-HETE (12-LOX metabolites) and PGE2 (COX-2 metabolite) significantly enhanced thymidine incorporation, suggesting a role for these enzymes in the regulation of A431 cell proliferation. Further studies on the mechanism of cell death by baicalein and celecoxib revealed that the induction of apoptosis in A431 cells was associated with reduction in the Bcl-2/Bax ratio, release of cytochrome c, activation of caspase-3 and PARP cleavage. The apoptosis induced by baicalein and celecoxib was mediated by down regulation of ERK and PI3K-Akt pathways. Further, 12-(R)-HETE, 12-(S)-HETE and PGE2 upregulated the p-ERK and p-Akt levels, suggesting the involvement of ERK and Akt pathways in the 12-LOX- and COX-2-mediated regulation of growth in A431 cells. Our findings suggest that 12-R-LOX and COX-2 play a critical role in the regulation of growth in epidermoid carcinoma and that their inhibitors may be of potential therapeutic importance. © 2009 John Wiley & Sons A/S.
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    Inhibition of 12-LOX and COX-2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K-Akt signalling pathways
    ( 2009-11-01) Agarwal, Smita ; Achari, Chandrani ; Praveen, D. ; Roy, Karnati R. ; Reddy, Gorla Venkateswara ; Reddanna, Pallu
    Eicosanoids, the oxygenated metabolites of arachidonic acid (AA), mediate a variety of human diseases, such as cancer, inflammation and arthritis. To evaluate the role of eicosanoids in epidermoid carcinoma, the expression of AA metabolizing enzymes, such as lipoxygenases (LOXs) and cyclooxygenases (COXs), was analysed in a human epidermoid carcinoma cell line (A431). These studies revealed overexpression of 12-R-LOX and COX-2 in A431 cells. Baicalein (a 12-LOX inhibitor) and celecoxib (a COX-2 inhibitor) significantly reduced thymidine incorporation, whereas 12-(R)-HETE and 12-(S)-HETE (12-LOX metabolites) and PGE2 (COX-2 metabolite) significantly enhanced thymidine incorporation, suggesting a role for these enzymes in the regulation of A431 cell proliferation. Further studies on the mechanism of cell death by baicalein and celecoxib revealed that the induction of apoptosis in A431 cells was associated with reduction in the Bcl-2/Bax ratio, release of cytochrome c, activation of caspase-3 and PARP cleavage. The apoptosis induced by baicalein and celecoxib was mediated by down regulation of ERK and PI3K-Akt pathways. Further, 12-(R)-HETE, 12-(S)-HETE and PGE2 upregulated the p-ERK and p-Akt levels, suggesting the involvement of ERK and Akt pathways in the 12-LOX- and COX-2-mediated regulation of growth in A431 cells. Our findings suggest that 12-R-LOX and COX-2 play a critical role in the regulation of growth in epidermoid carcinoma and that their inhibitors may be of potential therapeutic importance. © 2009 John Wiley & Sons A/S.