Search

The present study explores the potential of the anti-neoplastic action of aspirin in a transplantable murine tumour model of a spontaneously originated T-cell lymphoma designated as Dalton's lymphoma. The antitumour action of aspirin administered to tumour-bearing mice through oral and/or intraperitoneal (intratumoral) routes was measured via estimation of survival of tumour-bearing mice, tumour cell viability, tumour progression and changes in the tumour microenvironment. Intratumour administration of aspirin examined to assess its therapeutic potential resulted in retardation of tumour progression in tumour-bearing mice. Oral administration of aspirin to mice as a prophylactic measure prior to tumour transplantation further primed the anti-neoplastic action of aspirin administered at the tumour site. The anti-neoplastic action of aspirin was associated with a decline in tumour cell survival, augmented induction of apoptosis and nuclear shrinkage. Tumour cells of aspirin-treated mice were found arrested in G0/G1 phase of the cell cycle and showed nuclear localization of cyclin B1. Intratumoral administration of aspirin was accompanied by alterations in the biophysical, biochemical and immunological composition of the tumour microenvironment with respect to pH, level of dissolved O2, glucose, lactate, nitric oxide, IFNγ (interferon γ ), IL-4 (interleukin-4), IL-6 and IL-10, whereas the TGF-γ (tumour growth factor-γ) level was unaltered. Tumour cells obtained from aspirin-treated tumourbearing mice demonstrated an altered expression of pH regulators monocarboxylate transporter-1 and V-ATPase along with alteration in the level of cell survival regulatory molecules such as survivin, vascular endothelial growth factor, heat-shock protein 70, glucose transporter-1, SOCS-5 (suppressor of cytokine signalling-5), HIF-1α (hypoxiainducible factor-1α) and PUMA (p53 up-regulated modulator of apoptosis). The study demonstrates a possible indirect involvement of the tumour microenvironment in addition to a direct but limited anti-neoplastic action of aspirin in the retardation of tumour growth [ABSTRACT FROM AUTHOR]

Abstract: Mechanisms underlying tumor growth retarding effect of proton pump inhibitor pantoprazole (PPZ) on a murine T cell lymphoma, designated as Dalton''s lymphoma (DL), were investigated. In vivo administration of PPZ to tumor-bearing mice resulted in retardation of tumor progression owing to an inhibition of tumor cell survival and augmented apoptosis. An alteration in the parameters of tumor microenvironment and modulation in the expression of cell growth regulatory molecules is indicated to be involved in PPZ-dependent tumor growth retardation. These findings will help in optimizing therapeutic strategies against cancer using PPZ. [Copyright &y& Elsevier]

Abstract: Proton pump inhibitors (PPI) are being considered for antineoplastic therapeutic regimens due to their ability to reverse H+ homeostasis in tumor microenvironment and induce tumor cell death. In order to explore additional mechanism(s) underlying antitumor action of PPI, the present investigation was undertaken to investigate the effect of a PPI pantoprazole (PPZ) on the activation of tumor-associated macrophages (TAM) to tumoricidal state in a murine model of a transplantable T cell lymphoma of spontaneous origin growing in ascitic form. In vivo administration of PPZ to tumor-bearing mice resulted in an enhanced TAM recruitment in tumor microenvironment with M1 macrophage phenotype and augmented activation of TAM to tumoricidal state along with expression of tumor cytotoxic molecules. The study also demonstrates that TAM activating action of PPZ is of indirect nature mediated via its antitumor activity, reversal of tumor-induced immunosuppression and a consequent shift of cytokine balance in the tumor microenvironment favoring polarization of macrophages to M1 type. The study further shows that adoptive transfer of TAM harvested from PPZ-administered tumor-bearing hosts causes an efficient retardation of tumor growth. Possible mechanisms and significance of these observations with respect to the designing of antitumor therapy using PPI are discussed. [ABSTRACT FROM AUTHOR]

Problem We previously demonstrated the existence of gender dimorphism in a murine tumor model with respect to the growth of a spontaneous T-cell lymphoma designated as Dalton’s lymphoma and several aspects of host-tumor interaction. We also demonstrated the involvement of macrophages in manifestation of gender-dependent differential tumor growth [ J Reprod Immunol 2005; 65:17, Cancer Invest 2006; 24:1, J Biomed Sci 2007 (in press), J Reprod Immunol 2007; 74:90 ]. Although monocytes/macrophages of tumor-bearing hosts have been used to differentiate into macrophage-derived dendritic cells for various applications in the immunotherapy of cancer, it remains unclear if macrophages show a gender-dependent differential response to the signals of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for differentiation to cells with dendritic cell morphology (MO-DC) and if these MO-DC have a gender-dependent differential therapeutic efficacy in inhibiting tumor growth. Method of study Peritoneal macrophage obtained from male and female mice were incubated in vitro for a period of 7 days in a medium containing GM-CSF (800 IU/mL) and IL-4 (500 IU/mL) followed by incubation for further 24 hr in medium alone or containing lipopolysaccharide (LPS; 10 ng/mL) to differentiate into cells with DC morphology (MO-DC). The MO-DC thus obtained were used to check a variety of phenotypic and functional parameters related to their gender-dependent anti-tumor activity. Results The MO-DC obtained from male mice showed a better response to GM-CSF and IL-4 treatment and activation by LPS for differentiating into cells with DC phenotype compared with that of female mice. MO-DC of male mice showed a comparatively higher tumoricidal activity, expression of DC markers [chemokine receptor-5 (CCR-5), ICAM-1 (CD-54) and CD-80], MLR, pinocytosis and production of NO, IFN-γ and TNF-α. Adoptive transfer of MO-DC obtained from male mice to tumor-bearing mice resulted in a longer prolongation of survival duration and a better retardation of tumor growth compared with the MO-DC obtained from female mice. Conclusion To the best of our knowledge, this is the first report of its kind to demonstrate the existence of gender dimorphism in the antitumor and other accessory functions of macrophages differentiated in vitro into cells with DC morphology. These observations may have long lasting clinical significance in developing gender-specific protocols regarding the use of MO-DC in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

It was been previously reported that thyalpha1 can be used to activate monocytes, BMDM and TAM. However, the effect of thyalpha1 on other tissue macrophages has not been investigated. Moreover, there is no report about the use of thyalpha1-treated macrophages in adoptive immunotherapy of cancer. In view of these observations in the present study, we checked the response of various tissue macrophages to thyalpha1 for activation. Tissue macrophages showed differential response to thyalpha1; moreover, adoptive transfer of peritoneal macrophages treated with thyalpha1 to mice bearing spontaneous T-cell lymphoma designated as Dalton's lymphoma (DL) resulted in the prolongation of the survival time of tumor-bearing mice. The mechanism of macrophage therapy-dependent tumor regression was enhanced antitumor activity of macrophages in response to thyalpha1 treatment via their production of macrophage-activating cytokines that act in autocrine manner. These results will help in the development of immunotherapy against tumor based on activation of macrophage with thyalpha1. [ABSTRACT FROM AUTHOR]

Methyl jasmonate (MJ) displays antineoplastic potential against numerous neoplastic cells. However, several mechanistic aspects of its antineoplastic action against malignancies of T cell origin remain elusive. The present investigation reports the novel targets of MJ and mechanistic pathways of MJ-mediated antineoplastic and chemosensitizing action against tumor cells derived from murine T-cell lymphoma, designated as Dalton's lymphoma (DL). The present study demonstrates that MJ directly docks to HIF-1α, hexokinase 2, and Hsp70 at prominent binding sites. MJ exhibits tumoricidal action against tumor cells via induction of apoptosis and necrosis through multiple pathways, including declined mitochondrial membrane potential, enhanced expression of ROS, altered pH homeostasis, an elevated level of cytosolic cytochrome c , and modulated expression of crucial cell survival and metabolism regulatory molecules. Additionally, this study also reports the chemosensitizing ability of MJ against T cell lymphoma accompanied by a declined expression of MDR1. This study sheds new light by demonstrating the implication of novel molecular mechanisms underlying the antitumor action of MJ against T-cell lymphoma and hence has immense translational significance. [ABSTRACT FROM AUTHOR]

Orlistat, an inhibitor of fatty acid synthase (FASN), acts as an antitumor agent by blocking de novo fatty acid synthesis of tumor cells. Although, myelopoiesis also depends on de novo fatty acid synthesis, the effect of orlistat on differentiation of macrophages, which play a central role in host’s antitumor defence, remains unexplored in a tumor-bearing host. Therefore, the present investigation was undertaken to examine the effect of orlistat administration on macrophage differentiation in a T cell lymphoma bearing host. Administration of orlistat (240 mg/kg/day/mice) to tumor-bearing mice resulted in a decline of tumor load accompanied by an augmentation of bone marrow cellularity and survival of bone marrow cells (BMC). The expression of apoptosis regulatory caspase-3, Bax and Bcl2 was modulated in the BMC of orlistat-administered tumor-bearing mice. Orlistat administration also resulted in an increase in serum level of IFN-γ along with decreased TGF-β and IL-10. BMC of orlistat-administered tumor-bearing mice showed augmented differentiation into macrophages accompanied by enhanced expression of macrophage colony stimulating factor (M-CSF) and its receptor (M-CSFR). The macrophages differentiated from BMC of orlistat-administered mice showed characteristic features of M1 macrophage phenotype confirmed by expression of CD11c, TLR-2, generation of reactive oxygen species, phagocytosis, tumor cell cytotoxicity, production of IL-1,TNF-α and nitric oxide. These novel findings indicate that orlistat could be useful to support myelopoesis in a tumor-bearing host. [ABSTRACT FROM AUTHOR]

Abstract: Pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase (PDH) activity and thus promotes energetic switch from mitochondrial glucose oxidation to cytoplasmic glycolysis in cancerous cells (a phenomenon known as the ‘Warburg effect’) for their energy need, which facilitates the cancer progression by resisting induction of apoptosis and promoting tumor metastasis. Thus, in the present investigation, we explored the molecular mechanisms of the tumoricidal action of dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, on cells of a murine T cell lymphoma, designated as Dalton’s lymphoma (DL). In vitro treatment of tumor cells with DCA inhibited their survival accompanied by a modulation of the biophysical composition of tumor-conditioned medium with respect to pH, glucose and lactate. DCA treatment also altered expression of HIF1-α and pH regulators: VATPase and MCT1 and production of cytokines: IL-10, IL-6 and IFN-γ. Moreover, we also observed an alteration in the expression of other apoptosis and cell survival regulatory molecules: PUMA, GLUT1, Bcl2, p53, CAD, caspase-3 and HSP70. The study discusses the role of novel molecular mechanisms underlying DCA-dependent inhibition of tumor cell survival. This study shows for the first time that DCA-dependent alteration of tumor cell survival involves altered pH homeostasis and glucose metabolism. Thus, these findings will provide a new insight for therapeutic applications of DCA as a novel antineoplastic agent against T cell lymphoma. [Copyright &y& Elsevier]

Abstract: The present investigation studied the effect of aspirin administration in tumor-bearing hosts on bone marrow cellularity and myelopoiesis. Aspirin administration to mice bearing a transplantable T-cell lymphoma, designated as Dalton''s lymphoma (DL), augmented proliferation of bone marrow cells (BMC). BMC of aspirin-administered tumor-bearing mice were found to be predominantly in the S phase of cell cycle releasing them from G0/G1 arrest. Aspirin-exposed BMC also showed an altered expression of survival and cell cycle regulatory proteins p53, bcl2, caspase-activated deoxyribonuclease (CAD), cyclin B1 and cyclin D. Moreover, the BMC of aspirin-administered tumor-bearing mice showed an augmented colony-forming ability and differentiation in the macrophage lineage with an activated phenotype of bone marrow-derived macrophages (BMDM) with respect to macrophage-mediated tumoricidal activity and production of nitric oxide, IL-1β, TNFα and VEGF. On the other hand aspirin administration to normal mice showed little effect on bone marrow cellularity and myeloid differentiation. In this model, aspirin had a myelopoetic action in tumor-bearing host. [Copyright &y& Elsevier]

Abstract: Using a murine model of a T cell lymphoma, in the present study, we report that tumor growth retarding action of curcumin involves modulation of some crucial parameters of tumor microenvironment regulating tumor progression. Curcumin-administration to tumor-bearing host caused an altered pH regulation in tumor cells associated with alteration in expression of cell survival and apoptosis regulatory proteins and genes. Nevertheless, an alteration was also observed in biophysical parameters of tumor microenvironment responsible for modulation of tumor growth pertaining to hypoxia, tumor acidosis, and glucose metabolism. The study thus sheds new light with respect to the antineoplastic action of curcumin against a tumor-bearing host with progressively growing tumor of hematological origin. This will help in optimizing application of the drug and anticancer research and therapy. [Copyright &y& Elsevier]

Abstract: Aspirin is an anti-inflammatory drug demonstrated to possess a tremendous anticancer potential. As progression of some tumors is influenced by sex hormones, we investigated if the antineoplastic action of aspirin shows gender dependence. Using a murine model of T-cell lymphoma, the present investigation was undertaken to study if the antitumor actions of aspirin against lymphoma cells display gender dimorphism. The findings of the present investigation indicate that aspirin administration to male and female tumor-bearing hosts resulted in gender dependent differential tumor growth retardation. Such gender dichotomy of aspirin''s antitumor action was associated with a differential impact on cell cycle progression and expression of cell survival regulatory molecules. Aspirin administration was also found to modulate crucial parameters of tumor microenvironment, including contents of glucose, lactate and cell growth regulatory cytokines, in a gender specific manner. Aspirin was found to reverse estrogen-dependent augmentation of tumor cell survival in vitro. Taken together the results of the present study suggest that the antineoplastic action of aspirin is gender-dependent and should be considered in designing of gender-specific therapeutic applications of aspirin. [Copyright &y& Elsevier]