Department of Animal Biology

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Browsing Department of Animal Biology by Author "Achari, Chandrani"
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    Anti-leukemic effects of gallic acid on human leukemia K562 cells: Downregulation of COX-2, inhibition of BCR/ABL kinase and NF-κB inactivation
    ( 2012-04-01) Chandramohan Reddy, T. ; Bharat Reddy, D. ; Aparna, A. ; Arunasree, Kalle M. ; Gupta, Geetika ; Achari, Chandrani ; Reddy, G. V. ; Lakshmipathi, V. ; Subramanyam, A. ; Reddanna, P.
    Gallic acid (GA) induces apoptosis in various cancer cell lines. In this study, we investigated the apoptotic activity induced by GA on chronic myeloid leukemia (CML) cell line-K562 and the underlying mechanism. GA reduced the viability of K562 cells in a dose and time dependent manner. GA led to G 0/G 1 phase arrest in K562 cells by promoting p21 and p27 and inhibiting the levels of cyclin D and cyclin E. Further studies indicated apoptosis with impaired mitochondrial function as a result of deranged Bcl-2/Bax ratio, leakage of cytochrome c and PARP cleavage along with DNA fragmentation and by up-regulating the expression of caspase-3. GA also activated the protein expressions of fatty acid synthase ligand and caspase-8. GA is more effective in imatinib resistant-K562 (IR-K562) cells (IC 50 4μM) than on K562 cells (IC 50 33μM). GA inhibited cyclooxygenase-2 (COX-2) in K562 as well as IR-K562 cells appears to be COX-2 involved in the suppression of growth. Interestingly, GA also inhibited BCR/ABL tyrosine kinase and NF-κB. In conclusion, GA induced apoptosis in K562 cells involves death receptor and mitochondrial-mediated pathways by inhibiting BCR/ABL kinase, NF-κB activity and COX-2. © 2012 Elsevier Ltd.
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    Anti-leukemic effects of gallic acid on human leukemia K562 cells: Downregulation of COX-2, inhibition of BCR/ABL kinase and NF-κB inactivation
    ( 2012-04-01) Chandramohan Reddy, T. ; Bharat Reddy, D. ; Aparna, A. ; Arunasree, Kalle M. ; Gupta, Geetika ; Achari, Chandrani ; Reddy, G. V. ; Lakshmipathi, V. ; Subramanyam, A. ; Reddanna, P.
    Gallic acid (GA) induces apoptosis in various cancer cell lines. In this study, we investigated the apoptotic activity induced by GA on chronic myeloid leukemia (CML) cell line-K562 and the underlying mechanism. GA reduced the viability of K562 cells in a dose and time dependent manner. GA led to G 0/G 1 phase arrest in K562 cells by promoting p21 and p27 and inhibiting the levels of cyclin D and cyclin E. Further studies indicated apoptosis with impaired mitochondrial function as a result of deranged Bcl-2/Bax ratio, leakage of cytochrome c and PARP cleavage along with DNA fragmentation and by up-regulating the expression of caspase-3. GA also activated the protein expressions of fatty acid synthase ligand and caspase-8. GA is more effective in imatinib resistant-K562 (IR-K562) cells (IC 50 4μM) than on K562 cells (IC 50 33μM). GA inhibited cyclooxygenase-2 (COX-2) in K562 as well as IR-K562 cells appears to be COX-2 involved in the suppression of growth. Interestingly, GA also inhibited BCR/ABL tyrosine kinase and NF-κB. In conclusion, GA induced apoptosis in K562 cells involves death receptor and mitochondrial-mediated pathways by inhibiting BCR/ABL kinase, NF-κB activity and COX-2. © 2012 Elsevier Ltd.
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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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    Chebulagic acid synergizes the cytotoxicity of doxorubicin in human hepatocellular carcinoma through COX-2 dependant modulation of MDR-1
    ( 2011-09-01) Achari, Chandrani ; Reddy, Gorla V. ; Reddy, T. C.M. ; Reddanna, Pallu
    Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) specific inhibitors are antiinflammatory agents that have also shown to be useful in anticancer therapy. The effects of chebulagic acid (CA), a benzopyran tannin from Terminalia chebula having COX-2/5-LOX dual inhibitory properties, on the sensitivity of doxorubicin (Dox) in human hepatocellular carcinoma cell line HepG2 were studied in the present investigation. CA increased the accumulation of Dox in a concentration dependant manner and also enhanced the cytotoxicity of Dox in HepG2 cells by 20 folds. Quantitation of interaction by calculating Combination Index (CI) showed a strong synergistic interaction between CA and Dox in terms of cell growth inhibition. Calculation of dose reduction index (DRI) for CA-Dox combinations also showed a significant decrease in the dosage of Dox in the presence of CA. The induction of multidrug resistance protein-1 (MDR-1) expression by PGE 2, a metabolite of COX-2, and its downregulation by COX-2 knockdown or CA implies that the enhanced sensitivity of HepG2 cells to doxorubicin by CA is mediated by the downregulation of MDR1 expression, via COX-2-dependent mechanism. Further studies reveal the inactivation of signal transduction pathways involving Akt, ERK, JNK and p38 and the transcription factor NF-κB in the CA induced down regulation of MDR1. The present study shows the efficacy of CA to overcome MDR-1 mediated drug resistance in HepG2 cells through COX-2 dependant modulation of MDR-1. © 2011 Bentham Science Publishers Ltd.
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    Design, synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors
    ( 2010-08-15) Reddy, Nimmanapalli P. ; Aparoy, Polamarasetty ; Reddy, T. Chandra Mohan ; Achari, Chandrani ; Sridhar, P. Ramu ; Reddanna, Pallu
    Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen-Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC50 at 4 μM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI50 at 9 μM) on breast cancer cell line, MCF-7. © 2010 Elsevier Ltd. All rights reserved.
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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.
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    Structure based drug design, synthesis and evaluation of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives as 5-lipoxygenase inhibitors
    ( 2012-01-01) Reddy, Nimmanapalli P. ; Chandramohan Reddy, T. ; Aparoy, Polamarasetty ; Achari, Chandrani ; Sridhar, P. Ramu ; Reddanna, Pallu
    A group of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives were designed using Site point connection method, synthesized and evaluated for their 5-Lipoxygenase (5-LOX) inhibitory activity. Hydrophobic site points in 5-LOX were considered for the study and substitutions were planned such that 4k will have strong hydrophobic group in the corresponding site point. Biological results supported the in silico prediction with compound 4k exhibiting good inhibition with IC 50 value of 8 μM against 5-LOX. The compounds 4j and 4k showed potent cytotoxic effects against various cancer cell lines (COLO-205, MDA-MB-231 and HepG2) but with no effect on normal cell line (HaCaT). The overall trend showed 4k as the most potent compound. Further studies demonstrated the protective effect of 4k in mouse Acute Lung Injury (ALI) model induced by lipopolysaccharide (LPS). © 2011 Elsevier Masson SAS. All rights reserved.