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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.


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.


Siveen K.S.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
International Immunopharmacology | Year: 2011

Thujone, a naturally occurring monoterpene, was found to enhance the total WBC count, bone marrow cellularity, number of α-esterase positive cells, number of plaque forming cells in spleen and circulating antibody titer in Balb/c mice (1 mg/kg body weight, intraperitoneally for 5 days). Thujone treatment enhanced proliferation of splenocytes and thymocytes, both in the presence and absence of specific mitogens. Administration of Thujone was found to stimulate the cell-mediated immunological response in normal and tumor bearing Balb/c mice. A significant enhancement in natural killer (NK) cell mediated cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent complement mediated cytotoxicity (ACC) in both normal as well as tumor-bearing animals was observed after the administration of Thujone. Production of cytokines such as IL-2 and IFN-γ was significantly enhanced by the administration of Thujone. The stimulatory effect of Thujone on cytotoxic T lymphocyte (CTL) generation was determined by Winn's neutralization assay using CTL sensitive EL4 thymoma cells. Thujone treatment showed a significant increase in CTL production in both the in vivo and in vitro models, as indicated by a significant increase in the life span of tumor bearing animals. All these results indicate that administration of Thujone could enhance the immune response of mice. There was a significant reduction in solid tumor development, mediated by the presence of alert immune responses during Thujone administration. © 2011 Elsevier B.V.


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.


Siveen K.S.,Amala Cancer Research Center | Kuttan G.,Amala Cancer Research Center
Canadian Journal of Physiology and Pharmacology | Year: 2011

The antimetastatic potential of thujone, a naturally occurring monoterpene, was evaluated. Metastasis was induced in C57BL/6 mice by injecting highly metastatic B16F-10 melanoma cells through the lateral tail vein. Administration of thujone (1 mg·(kg body weight) -1), prophylactically and simultaneously with tumor induction, inhibited tumor nodule formation in the lungs by 59.45% and 57.54%, respectively, with an increase in the survival rate (33.67% and 32.16%) of the metastatic tumor bearing animals. These results correlated with biochemical parameters such as lung collagen hydroxyproline, hexosamine and uronic acid contents, serum sialic acid and γ-glutamyl transpeptidase levels, and histopathological analysis. Treatment with thujone downregulated the production of proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and granulocyte-monocyte colony-stimulating factor. Thujone administration downregulated the expression of matrix metalloproteinase (MMP)-2, MMP-9, extracellular signal-regulated kinase (ERK)-1, ERK-2, and vascular endothelial growth factor (VEGF) and also upregulated the expression of nm-23, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 in the lung tissue of metastasis-induced animals. Treatment with thujone inhibited the activity of MMP-2 and MMP-9 in gelatin zymographic analysis. Thujone treatment significantly inhibited the invasion of B16F-10 melanoma cells across the collagen matrix in a Boyden chamber. Thujone also inhibited the adhesion of tumor cells to collagen- coated microtire plate wells and the migration of B16F-10 melanoma cells across a polycarbonate filter in vitro. These results indicate that Thujone can inhibit the lung metastasis of B16F-10 cells through inhibition of tumor cell proliferation, adhesion, and invasion, as well as by regulating expression of MMPs, VEGF, ERK-1, ERK-2, TIMPs, nm23, and levels of proinflammatory cytokines and IL-2 in metastatic animals.

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