Amala Cancer Research Center

Trichūr, India

Amala Cancer Research Center

Trichūr, India
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Hamsa T.P.,Amala Cancer Research Center | Hamsa T.P.,University of Florida | Kuttan G.,Amala Cancer Research Center
Phytotherapy Research | Year: 2012

The present study demonstrated the potential antimetastatic and antiinvasive effect of berberine using both in vivo mouse lung metastasis and in vitro models. Administration of berberine resulted in significant suppression of B16F-10 melanoma induced tumor nodule formation and enhanced the survival of tumor-bearing mice. Berberine treatment also decreased various biochemical parameters associated with lung metastasis. These inhibitory actions may be due to the significant suppression of several signaling molecules such as ERK1/2, NF-κB, ATF-2 and CREB involved in the transcription signaling pathways for MMP gene expression. It could also inhibit the migration and invasion of highly metastatic murine melanoma cells in a dose-dependent manner in vitro. The results clearly show that berberine could significantly inhibit experimental lung metastasis produced by intravenous injection of B16F-10 melanoma cells and this effect could be linked to the down-regulation of metastasis-related signaling molecules. Copyright © 2011 John Wiley & Sons, Ltd.


Hamsa T.P.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
European Journal of Pharmacology | Year: 2010

Harmine is a beta-carboline alkaloid present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In this study, we demonstrated the anti-angiogenic activity of harmine using in vivo and in vitro assay systems. In vivo anti-angiogenic activity was studied using B16F-10 melanoma cells which induced capillary formation in C57BL/6 mice. Intraperitoneal administration of harmine at 10. mg/kg body weight significantly decreased tumour directed capillary formation. A drastic elevation in serum pro-angiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide (NO) and pro-inflammatory cytokines in angiogenesis induced animals was significantly decreased by harmine treatment. At the same time harmine increased anti-tumour factors like interleukin-2 (IL-2) and tissue inhibitor metalloprotease (TIMP). Moreover nuclear factor (NF)-κB and other transcription factors like CREB, ATF-2 involved in tumour development and angiogenesis were also inhibited by harmine. Various in vitro assays also supported the anti-angiogenic activity of harmine. It reduced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Direct treatment of the harmine also inhibited microvessel outgrowth from the rat aortic ring. Production of other factors by tumour cells which are involved in angiogenesis like cyclooxygenase (COX-2), inducible nitric oxide synthase (iNOS) and matrix metalloproteases (MMPs) were also decrease by the treatment with harmine. Our data suggest that harmine may be a strong angiogenic inhibitor with the ability to decrease the proliferation of vascular endothelial cells and to reduce expression of various pro-angiogenic factors. © 2010 Elsevier B.V.


Pratheeshkumar P.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
European Journal of Pharmacology | Year: 2011

Angiogenesis is a crucial step in the growth and metastasis of cancers. Antiangiogenic activity of nomilin was studied using in vivo as well as in vitro models. Nomilin significantly inhibited tumor directed capillary formation. Serum proinflammatory cytokines such as IL-1β, IL-6, TNF-α and GM-CSF and also serum NO levels were significantly reduced by the treatment of nomilin. Administration of nomilin significantly reduced the serum level of VEGF, a proangiogenic factor and increased the antiangiogenic factors IL-2 and TIMP-1. In vitro studies using rat aortic ring assay showed that administration of nomilin at non-toxic concentrations significantly inhibited microvessel sprouting. Studies using human umbilical vein endothelial cells clearly demonstrated that administration of nomilin significantly retarded endothelial cell proliferation, migration, invasion and tube formation. These data clearly demonstrate the antiangiogenic potential of nomilin by downregulating the activation of MMPs, production of VEGF, NO and proinflammatory cytokines as well as upregulating IL-2 and TIMP. © 2011 Elsevier B.V. All rights reserved.


Jeena K.,Amala Cancer Research Center | Liju V.B.,Amala Cancer Research Center | Kuttan R.,Amala Cancer Research Center
International Journal of Pharmacy and Pharmaceutical Sciences | Year: 2015

Objective: To evaluate the cytotoxicty and antitumor activity of ginger essential oil (GEO). Methods: Cytotoxicity towards Dalton’s Lymphoma Ascites (DLA) and Ehrlich Ascites Carcinoma (EAC) cell lines were evaluated by trypan blue exclusion method. In vitro cytotoxicity of GEO to L929 cells in culture were checked by MTT assay. The antitumor activity of GEO was determined by using DLA cell line induced solid tumor and EAC cell line induced ascites tumor model in mice and its comparison with standard anticancer drug cyclophosphamide. Results: GEO showed potent in vitro cytotoxic activity against DLA and EAC cell lines. IC50 value for DLA cell line was 11 μg/ml and for EAC cell lines 18 μg/ml. The IC50of GEO was found to be 41 μg/ml against the L929 cell lines and to Vero cells was found to be ˃100 ug/ml. The treatment with GEO (500 mg/kg and 1000 mg/kg body weight) significantly reduced the volume of solid tumor development by 54.4% and 62.4% respectively. The life span was increased up to 50% in 1000 mg/kg b. wt GEO treated ascites tumor induced animals. Conclusion: This indicates the significant in vitro cytotoxic and antitumor properties of GEO suggesting its potential use as an anticancer agent. © 2015, International Journal of Pharmacy and Pharmaceutical Sciences. All rights reserved.


Hamsa T.P.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
Drug and Chemical Toxicology | Year: 2012

Berberine, a naturally occurring isoquinoline alkaloid, is present in a number of important medicinal plants. Berberine has a wide range of biochemical and pharmacological effects, including anticancer effects. In this study, we elucidated the mechanism of antiangiogenic activity of berberine using in vivo and in vitro models. In vivo antiangiogenic activity was studied using B16F-10 melanoma cells and induced capillary formation in C57BL/6 mice. Berberine, at 10mg/kg body weight, showed significant inhibition in tumor-directed capillary formation and in various proangiogenic factors, such as vascular endothelial growth factor (VEGF), and proinflammatory mediators, such as interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF), which are involved in tumor angiogenesis. At the same time, it could also increase antitumor factors, such as IL-2 and tissue-inhibitor metalloproteinase (TIMP) levels in the serum. Berberine could also inhibit endothelial motility, migration, tube formation, and vessel sprouting from rat aortic ring in vitro. Further, berberine inhibited various transcription factors involved in tumor development and angiogenesis, such as NF-κB, c-Fos, CREB, and ATF-2. mRNA expression levels of proangiogenic factors, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor (HIF), were also downregulated in tumor cells after treatment with berberine. Drastically elevated expressions of HIF and VEGF mRNA by tumor cells under hypoxic conditions were also decreased after treatment with berberine. This result clearly demonstrates that the antiangiogenic activity of berberine is mainly mediated through the inhibition of various proinflammatory and pro-angiogenic factors and the major ones are HIF, VEGF, COX-2, NO, NF-κB, and proinflammatory cytokines. © 2012 Informa Healthcare USA, Inc.


Ajith T.A.,Amala Institute of Medical science | Janardhanan K.K.,Amala Cancer Research Center
Food and Chemical Toxicology | Year: 2011

Mutations are one of the important factors contributing to oncogenesis. Somatic mutations have been detected in oncogenes and tumor suppressor genes in various types of cancers. In vitro antimutagenic activity of ethyl acetate extract of macro fungus, Phellinus rimosus was evaluated by Ames' mutagenicity assay. The effect was evaluated against the direct acting mutagens (sodium azide, N-methyl-N'-nitro-N-nitrosoguanidine, doxorubicin and 4-nitro-o-phenylenediamine) and mutagen needing activation (2-acetyl aminofluorine, and benzo[. a]pyrene). The extract was significantly (p<0.05) and dose dependently effective against direct acting mutagens and mutagen needing activation. Among the antimutagenic activity against directly acting mutagens, effect was found to be highest against doxorubicin-induced mutation. The antimutagenic effect of the extract against indirect acting mutagen in the presence of mammalian metabolic activation system was also found to be significant (p<0.01). The background bacterial growth and number of revertant colonies in the extract alone treated plate with or with out metabolic activator was almost same as that of spontaneous revertants. This indicated the non-toxic nature of the extract. The effect was partially ascribed to the antioxidant activity. The results of the study suggest the possible antitumor mechanisms of P. rimosus. © 2011 Elsevier Ltd.


Liju V.B.,Amala Cancer Research Center | Jeena K.,Amala Cancer Research Center | Kuttan R.,Amala Cancer Research Center
Food and Chemical Toxicology | Year: 2013

The present study investigated the acute, subchronic and genotoxicity of turmeric essential oil (TEO) from Curcuma longa L. Acute administration of TEO was done as single dose up to 5. g of TEO per kg body weight and subchronic toxicity study for thirteen weeks was done by daily oral administration of TEO at doses 0.1, 0.25 and 0.5. g/kg b.wt. in Wistar rats. There were no mortality, adverse clinical signs or changes in body weight; water and food consumption during acute as well as subchronic toxicity studies. Indicators of hepatic function such as aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were unchanged in treated animals compared to untreated animals. Oral administration of TEO for 13. weeks did not alter total cholesterol, triglycerides, markers of renal function, serum electrolyte parameters and histopathology of tissues. TEO did not produce any mutagenicity to Salmonella typhimurium TA-98, TA-100, TA-102 and TA-1535 with or without metabolic activation. Administration of TEO to rats (1. g/kg b.wt.) for 14. days did not produce any chromosome aberration or micronuclei in rat bone marrow cells and did not produce any DNA damage as seen by comet assay confirming the non toxicity of TEO. © 2012 Elsevier Ltd.


Pratheeshkumar P.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
Inflammopharmacology | Year: 2010

Cyclophosphamide (CTX) is a widely used antineoplastic drug, which could cause toxicity to normal cells due to its toxic metabolites. The use of CTX in treating cancer patients is limited due to its severe toxicity induced mainly by oxidative stress. The present study reports the protective role of Vernonia cinerea L. against the CTX-induced toxicity in Balb/c mice. Intraperitoneal administration of the extract significantly increased the total WBC Count, bone marrow cellularity, α-esterase positive cells, and weights of lymphoid organs in CTX-treated animals, when compared with CTX control mice. Administration of V. cinerea was found to reduce the enhanced level of alkaline phosphatase, glutamate pyruvate transaminase, lipid peroxidation, and also significantly increased the reduced glutathione level in CTX-treated animals. Histopathological analysis of small intestine also suggests that extract could reduce the CTX-induced intestinal damage. The level of proinflammatory cytokine TNF-α, which was elevated during CTX administration, was significantly reduced by the V. cinerea extract administration. The lowered levels of other cytokines like IFN-γ, IL-2, GM-CSF, after CTX treatment were also found to be increased by extract administration. Administration of V. cinerea did not compromise the anti-neoplastic activity of CTX. Infact, there was a synergistic action of CTX and V. cinerea in reducing the solid tumors in mice. Methanolic extract of V. cinerea given intraperitoneally (i.p.) showed a significant chemoprotective activity without compromising the chemotherapeutic efficacy of CTX, indicating its possible use as an adjuvant during chemotherapy. © 2010 Springer Basel AG.


Kanjoormana M.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
Integrative Cancer Therapies | Year: 2010

Angiogenesis, the formation of new capillaries from preexisting vessels, is essential for tumor progression. Ursolic acid inhibited the tumor-associated capillary formation in C57BL/6 mice induced by highly metastatic B16F-10 melanoma cells. The levels of serum vascular endothelial growth factor (VEGF), NO, and proinflammatory cytokines were significantly reduced in ursolic acid-treated animals compared with those in control animals. The diminished expressions of VEGF and iNOS genes in B16F-10 melanoma cells treated with nontoxic concentrations of ursolic acid support these observations; the serum TIMP-1 (tissue inhibitor of metalloproteinase-1) and IL-2 (interleukin-2) levels were significantly elevated after the ursolic acid treatment. Nontoxic concentrations of ursolic acid toward human umbilical vein endothelial cells (HUVEC) were determined by MTT (methylthiazol tetrazolium) assay, and these nontoxic concentrations were selected for the in vitro studies. Nontoxic concentrations of ursolic acid inhibited vessel growth from the rat aortic ring. 3H-thymidine proliferation assay clearly showed the inhibitory effect of ursolic acid on the proliferation of HUVECs in vitro. Ursolic acid significantly inhibited endothelial cell migration and invasion. The role of metalloproteinases has been shown to be important in angiogenesis; therefore, gelatin zymography was performed to determine whether ursolic acid affected protease activity. Gelatin zymographic analysis showed the inhibitory effect of ursolic acid on the protein expression of matrix metalloproteinases MMP-2 and MMP-9. The above observation shows the antiangiogenic activity of ursolic acid. © The Author(s) 2010.


Hamsa T.P.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
Chinese Medicine | Year: 2011

Background: Harmine is a beta-carboline alkaloid from the plant Peganum harmala. Previous studies found that harmine inhibited metastasis of B16F-10 melanoma cells. This study aims to elucidate the role of harmine in apoptosis of B16F-10 cells.Methods: B16F-10 melanoma cells were treated in the presence and absence of harmine in vitro. Morphological changes, cell cycle and expression of various pro and anti- apoptotic genes were analyzed for the study of apoptosis.Results: Morphological observation and DNA laddering assay showed that harmine treated cells displayed marked apoptotic characteristics, such as nuclear fragmentation, appearance of apoptotic bodies and DNA laddering fragment. TUNEL assay and flow cytometric analysis also confirmed apoptosis. Furthermore, RT-PCR analysis showed that harmine induced apoptosis in B16F-10 melanoma cells by up-regulating Bax and activating Caspase-3, 9 and p53 and down-regulating Bcl-2. Harmine also up-regulated Caspase-8 and Bid, indicating that harmine affected both extrinsic and intrinsic pathways of apoptosis. This study also showed inhibitory effects of harmine on some transcription factors and pro- inflammatory cytokines that protect cell from apoptosis.Conclusion: Harmine activates both intrinsic and extrinsic pathways of apoptosis and regulates some transcription factors and pro-inflammatory cytokines. © 2011 Hamsa and Kuttan; licensee BioMed Central Ltd.

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