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Abstract: Proton pump inhibitors (PPI) are being proposed as potent antitumor agents, owing to their ability to specifically induce tumor cell death by reversing H+ ion homeostasis. As tumor growth induces myelosuppression in tumor-bearing hosts, it remains unclear if PPI can also modulate tumor-induced myelosuppression. Thus, we studied the effect of in vivo administration of pantoprazole (PPZ), a PPI, on myelopoiesis in a murine model of a transplantable T cell lymphoma, designated as Dalton’s lymphoma (DL). Intraperitoneal administration of PPZ to tumor-bearing mice resulted in an enhanced bone marrow cellularity, inhibited induction of apoptosis and augmented bone marrow cell (BMC) survival. BMC of PPZ-administered tumor-bearing mice showed elevated number of F4/80 positive cells, augmented colony forming ability and differentiation in bone marrow-derived macrophages (BMDM) with higher expression of F4/80 and CD11c markers. This study also presents evidences to indicate that PPZ-dependent augmentation of myelopoiesis in the tumor-bearing host is dependent on an enhanced expression of M-CSF and receptors for M-CSF & GM-CSF in BMC, along with a modulation in the expression of cell survival regulatory molecules PUMA, Bcl2, p53 and caspase-activated DNase (CAD). BMDM obtained from PPZ-administered tumor-bearing mice also showed an augmented expression of TLR-2, tumoricidal activity, production of NO and monokines: IL-1, IL-6 & TNF-α. The study discusses the possible mechanisms underlying PPZ-dependent augmentation of myelopoiesis. Taken together, the present study proposes that a PPZ-dependent alleviation of tumor-induced myelosuppression could contribute to an augmented myelopoiesis. [Copyright &y& Elsevier]

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]

In the present study using a transplantable murine T cell lymphoma designated as Dalton’s lymphoma, we investigated the role of oxygen, glucose and other environmental factors in evolution of altered survival responses in tumor cells during the late tumor-bearing stages. Tumor progression was observed to be associated with an improvement in the survival ability of tumor cells. Moreover, tumor serum and ascitic fluid obtained from the late tumor bearing stage was found to augment tumor cell survival in vitro, indicating that these humoral components of tumor bearing host contain factors capable of modulating tumor survival. Progressive tumor growth was also shown to be associated with depletion in glucose and oxygen content in the fluids of tumor microenvironment along with a concomitant augmentation in the production of lactate and lactate dehydrogenase. Moreover, tumor cells expressed higher amount of mRNA for inducible nitric oxide synthase, Hypoxia inducible factor-1 and 2 and Hsp70 and VEGF proteins during the late tumor bearing stages. Splenic macrophages and non-adherent splenic lymphocytes from tumor-bearing mice showed an increased production of IL-6, TGF-β, IFN-γ, IL-2R and VEGF during the late tumor-bearing stage, which could be implicated in the differential regulation of tumor growth in a tumor stage dependent manner. In conclusion, the observations of the present study suggest that factors contained in altered tumor microenvironment may act in concert to cause behavioral alterations in tumor cells, with respect to survival, during the course of the progression of a nonsolid T cell lymphoma. [ABSTRACT FROM AUTHOR]

Abstract: The present investigation was carried out to investigate if soluble mediators present in tumour microenvironment and systemic circulation of a tumour-bearing host can regulate growth properties and response of the cells of a T cell lymphoma to chemotherapeutic drug: cisplatin, depending on the stage of tumour progression. In order to investigate this, tumour cells of a murine T cell lymphoma, designated as Dalton’s lymphoma (DL), were incubated in vitro for 48h in the presence of ascitic fluid and serum obtained from cisplatin treated or untreated tumour hosts at early or late tumour-bearing stages and cell survival was estimated. It was observed that tumour serum and ascitic fluid showed a tumour stage-dependent differential ability to regulate tumour cell survival and susceptibility of the tumour cells to the cytotoxic action of cisplatin. A tumour stage-dependent qualitative and quantitative difference in the profile of cell survival regulating cytokines: IL-1, IL-2, IFN-γ, TNF-α, VEGF and TGF-β in the ascitic fluid and serum of the tumour-bearing host was observed to be associated with a tumour stage-dependent differential regulation of survival of tumour cells by modulation in the expression of growth regulating proteins: IL-2R, p53, CAD, Hsp70 and Bcl-2. Further the result also showed that production of IL-1, TNF-α, and NO by macrophages could be implicated in the differential action of tumour sera on the altered survival responses of tumour cells depending on the stage of tumour growth. Possible mechanisms involved in the tumour stage-dependent differential survival response of tumour cells and evolution of drug resistance are discussed. The finding of this investigation will have clinical implications in designing of therapeutic strategies for T cell lymphoma based on manipulation of tumour growth regulatory mediators present in the tumour microenvironment. [Copyright &y& Elsevier]

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]

The present study assessed central nervous system (CNS) and immune system changes in murine fetuses after cyclophosphamide (CP) exposure during intrauterine life. A single CP dose of 0, 10, or 20mg/kg body weight was administered by intraperitoneal inj ection to pregnant mice (20/group) on day 11 of gestation (GD 11) and fetuses were evaluated on day 19 of gestation (GD 19). Fetuses were examined for external changes, and then the brains and thymuses were removed for further evaluations of histological changes, protein content, apoptotic cell count, DNA fragmentation, and in vitro cell proliferation using 1 fetus/litter for each assessment. Brains and thymuses from CP-exposed fetuses were smaller in size and distorted in overall shape compared to those from the control group. Estimated mean protein content (mg/mL) of brains was decreased in the CP-exposed groups. In both brain cells and thymocytes there was an increase in mean apoptotic cell counts and in mean percent DNA fragmentation in the exposed groups. The in vitro cell proliferation assays conducted with cells from exposed fetuses exhibited a mean decrease in the number of both brain cells and thymocytes generated. These findings indicate that maternal CP treatment on GD 11 in mice results in marked fetal toxicity characterized by reduced live litter size, fetal body weights as well as brain and thymic weights and malformations which are accompanied by changes in brain protein content, brain and thymic apoptosis, DNA fragmentation and in vitro cell proliferation at term. [ABSTRACT FROM AUTHOR]

Abstract: Little information is available regarding the existence of gender dimorphism of tumor growth for most types of tumors. In a previous report we have demonstrated the existence of gender dimorphism in the growth of a murine T cell lymphoma, designated as Dalton''s lymphoma (DL); moreover, tumor-associated macrophages (TAM) were found to play a central role in the manifestation of gender dimorphism observed in the growth of this T cell lymphoma. In view of these observations, the present investigation was undertaken to study if gender dimorphism in the growth of a T cell tumor also could be associated with a gender-dependent differential myelopoiesis of bone marrow cells. We have demonstrated the existence of a gender dimorphism in the proliferation, apoptosis and myeloid differentiation of bone marrow cells obtained from male and female tumor-bearing hosts. Androgen and estrogen were found to alter directly the growth properties of bone marrow cells, as also determined by the use of receptor antagonists of these hormones, flutamide and tamoxifen. Bone marrow cells of male and female tumor-bearing hosts also showed a differential expression of the cell cycle and apoptosis regulatory protein p53 and macrophage-colony stimulating factor (M-CSF) genes. Bone marrow cells of male tumor-bearing hosts showed a predominant differentiation in the macrophage lineage whereas those of female tumor-bearing mice were in the granulocyte lineage. Bone marrow-derived macrophages (BMDM) from male and female tumor-bearing mice also showed the existence of gender dimorphism with respect to their differentiation and activation. These observations are of clinical significance with respect to understanding of the host–tumor relationship at the level of gender dimorphism of myelopoiesis. [Copyright &y& Elsevier]

Abstract: The present study investigates the effect of in vivo administration of alcoholic extract of Tinospora cordifolia whole plant (ALTC) on the proliferation and myeloid differentiation of bone marrow hematopoietic precursor cells in mice bearing a transplantable T cell lymphoma of spontaneous origin designated as Dalton''s lymphoma (DL). BMC obtained from ALTC administered DL-bearing mice showed an enhanced BMC proliferation and colony forming ability in vitro in response to L929 conditioned medium as a source of colony stimulating factor (CSF). The number of granulocyte–macrophages colony (CFU-GM) was predominantly higher in the cultures of BMC obtained from ALTC administered mice as compared to mice injected with PBS alone. An increase in the count of bone marrow derived macrophages (BMDM) from ALTC administered mice was also observed along with an increase in the count of tumor associated macrophages. The BMDM obtained from ALTC administered mice showed an enhanced response to signal of LPS for activation to produce IL-1 and TNF. This study indicates that the T. cordifolia can influence the myeloid differentiation of bone marrow progenitor cells and the recruitment of macrophages in response to tumor growth in situ. [Copyright &y& Elsevier]

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]

We and others previously have reported that extract prepared from medicinal plant Tinospora cordifolia shows a wide spectrum of immunoaugmentary effects. Tinospora cordifolia was shown to upregulate antitumor activity of tumor-associated macrophages (TAM). In this article we present evidence to show that an alcoholic extract of Tinospora cordifolia (ALTC) enhances the differentiation of TAM to dendritic cells (DC) in response to granulocyte/macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor. DC differentiated in vitro from TAM that were harvested from tumor-bearing mice after i.p. administration of ALTC (200 mg/kg body weight) 2 days posttumor transplantation shows an enhanced tumor cytotoxicity and production of tumoricidal soluble molecules like TNF, IL-1, and NO. Adoptive transfer of these TAMderived DC to Dalton's lymphoma-bearing mice resulted in prolongation of survival of tumor-bearing mice. This is the first report regarding the differentiation and antitumor functions of TAM-derived DC obtained from tumor-bearing host administered with ALTC. The possible mechanisms involved also are discussed. [ABSTRACT FROM AUTHOR]

We have previously suggested that thymosin α1 (thyα1), an immunomodulating thymic hormone, can activate tumor-associated macrophages to a tumoricidal state in a murine model bearing a transplantable T-cell lymphoma of spontaneous origin designated as Dalton’s lymphoma (DL). Since tumor-infiltrating dendritic cells (DC) also play an important role in the host’s antitumor response and are as such in an immunocompromised state in a tumor-bearing host, in the present investigation we studied if thyα1 is able to influence the differentiation of tumor-associated macrophages (TAM) into DC with granulocyte macrophage colony stimulating factor (GM-CSF), interleukin (IL)-4 and tumor necrosis factor (TNF) and whether these TAM-derived DC show enhanced antitumor activity. It was observed that DC generated from thyα1-administered tumor-bearing mice showed augmented antitumor activity in vitro. Adoptive immunotherapy using TAM-derived DC showed a significant delay in the tumor growth and a prolongation of the survival time in tumor-bearing mice. DC obtained from TAM of thyα1-administered mice also produced an enhanced amount of cytokines like IL-1 and TNF-α. This is the first study of its kind regarding the effect of thyα1 on the differentiation of DC from TAM and the role of TAM-derived DC in tumor progression. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present investigations were under taken to study whether the tumor-associated macrophages (TAM) of Dalton's lymphoma (DL), a spontaneous transplantable T cell lymphoma, can be activated by the alcoholic extract of medicinal plant Tinospora cordifolia (ALTC). Intraperitoneal administration of ALTC in DL-bearing mice not only augments the basic function of macrophages such as Phagocytosis as well as their antigen presenting ability and secretion of IL-1, TNF and RNI. The results of the present investigation also indicate that the intraperitoneal administration of ALTC slow down the tumor growth and increases the life span of tumor bearing host, thus showing its anti tumor effect through destabilizing the membrane integrity of DL cells directly or indirectly. This is the first study of it's kind regarding the effect of alcoholic extract of Tinospora cordifolia on the activation of tumor associated macrophages and showing the antitumor effect on the spontaneous T-cell lymphoma (DL), thus may have clinical implications. [ABSTRACT FROM AUTHOR]

Gangliosides (DLG) derived from a spontaneous T cell lymphoma (Dalton’s lymphoma) have been shown to impair the ability of lipopolysaccharide-activated macrophages to produce nitric oxide (NO). However, the mechanism and nature of this effect is not known. In this investigation, we sought to (1) determine whether the inhibitory action of DLG on macrophages is through the modulation of inducible nitric oxide synthase (iNOS) expression and (2) identify the possible mechanisms and signal transduction events underlying the inhibitory action of DLG. Immunoblot analysis of DLG-treated macrophages showed a decrease in iNOS expression. DLG also inhibited the production of monokines interleukin-1 and tumor necrosis factor by macrophages. However, the DLG-induced inhibition was reversible in nature. Studies showed that DLG-induced inhibition of macrophage activation could be blocked by sodium orthovanadate, indicating a role of phosphatase activity in ganglioside-induced inhibition. [Copyright &y& Elsevier]

Abstract: Background: Orlistat, a fatty acid synthase (FASN) inhibitor, has been demonstrated to inhibit tumor cell survival. However, the mechanism(s) of its tumor growth retarding action against malignancies of hematological origin remains unclear. It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs. Therefore, the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma. Methods: Tumor-bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin. Tumor progression and survival of tumor-bearing host were monitored along with analysis of tumor cell survival and apoptosis. Tumor ascitic fluid was examined for pH, NO and cytokines. Expression of genes and proteins was investigated by RT-PCR and western blot respectively. ROS was analyzed by DCFDA staining and FASN activity by spectrophotometry. Results: Orlistat administration to tumor-bearing mice resulted in tumor growth retardation, prolonged life span, declined tumor cell survival and chemosensitization to cisplatin. It was accompanied by increased osmotic fragility, modulated acidosis, expression of ROS, NO, cytokines, MCT-1 and VH+ ATPase, Bcl2, Caspase-3, P53, inhibited FASN activity and declined expression of MDR and MRP-1 proteins. Conclusion: Orlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype. General significance: These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin. [Copyright &y& Elsevier]

Abstract: Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. [Copyright &y& Elsevier]

Abstract: Background: De novo fatty acid synthesis catalyzed by fatty acid synthase (FASN) is crucial for tumor cell survival. Thus therapeutic targeting of FASN is considered as a novel antineoplastic strategy. However, little is understood in this respect regarding malignancies of hematological origin. The present investigation was therefore, undertaken to study the molecular mechanisms of the antitumor action of FASN inhibitor orlistat (tetrahydrolipstatin) using a murine model of a T cell lymphoma. Methods: The antitumor efficacy of orlistat was investigated in vitro by estimating cell survival by MTT assay and apoptosis by Wright Giemsa, TUNEL, Annexin-V/PI staining and % DNA fragmentation. Generation of reactive oxygen species (ROS) in tumor cells was studied using fluorescence microscopy. Expression of genes and proteins was carried out by RT-PCR and western blot analyses respectively. FASN and CPT-1 activity was estimated by spectrophotometer. Cytokines expression was analyzed by ELISA. Results: We report that inhibition of FASN with its specific inhibitor orlistat manifests tumor-specific inhibition of cell survival, accompanied by induction of apoptosis. Orlistat-treated tumor cells showed an altered ROS generation, shift in cytokine balance and modulated expression of cell survival regulatory molecules like HSP70, Bcl2, p53, PUMA, Caspase-3 and CAD. It was observed that IFN-γ mediates orlistat-dependent modulation of FASN expression. Conclusion and general significance: In this study, we report some of the so far unexplored novel aspects underlying the molecular mechanisms associated with orlistat-dependent modulation of tumor cell survival. These observations will help in designing antineoplastic therapeutic protocols using orlistat against malignancies of hematological origin. [Copyright &y& Elsevier]

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]

The objective of this study was to demonstrate thymic alterations produced by cyclophosphamide intervention during intrauterine life of murine fetus. Cyclophosphamide (CP) was administered to pregnant mice on day 11 of gestation in a single dose of 10 mg/kg body weight. Fetuses were dissected out on day 19 and studied for various effects on thymus. Thymus of fetuses exposed to cyclophosphamide showed thymic atrophy with retardation of thymic size and a remarkable shrinkage in lobular morphology. Histological studies showed a massive depletion of thymic cortex. Study of thymocytes revealed an increase in apoptotic cell count and percent DNA fragmentation along with a decrease in proliferation. Thymocytes obtained from fetuses of CP-treated mice showed a higher expression of caspase-activated DNase (CAD) indicating that the CP-dependent induction of apoptosis in thymocytes involved caspase pathway. The results of the present study may help in understanding the mechanism of the teratogenic effect of cyclophosphamide on thymus. [ABSTRACT FROM AUTHOR]

The present study was conducted to investigate the effect of prolactin (PRL) on the progressive growth of a T cell lymphoma. Using a murine model of a transplantable T cell lymphoma, designated as the Dalton's lymphoma (DL) it is shown that in vivo administration of PRL to tumor bearing mice reduces the survival duration of tumor-bearing host due to an augmentation of tumor growth. In vitro studies demonstrated that PRL directly stimulates the proliferation of DL cells in a dose and time dependent manner. PRL-treated DL cells showed an increase in cell size along with a decrease in cells with apoptotic morphology. Evidence also is presented to show the involvement of tumor and macrophage-derived cytokines: IL-1, IL-2, TGF-β, and M-CSF in PRL-dependent augmentation of tumor growth. Moreover, PRL treatment was found to inhibit Caspase-activated DNase (CAD) expression in DL cells indicating that PRL acts through modulation of caspase dependent pathway of apoptosis. The study is of novel significance as it demonstrates for the first time that PRL can promote growth of a T cell lymphoma involving host and tumor-derived tumor growth promoting cytokines. [ABSTRACT FROM AUTHOR]

Abstract: We have reported that the ascitic growth of a transplantable T cell lymphoma of spontaneous origin, designated as Dalton''s lymphoma (DL), is associated with a concomitant immunosuppression. We have also reported that progressive in vivo growth of DL resulted in an inhibition of macrophage functions. In present investigation we report that physical exercise by DL-bearing mice, on a treadmill on a daily basis for various time durations for 10 days, increased the life span along with an inhibition of tumor growth. A significant decrease in the volume of ascitic fluid and number of cells in the tumor was obtained in mice, which underwent exercise. DL cells obtained from exercised groups showed a decreased proliferation in vitro. An augmentation in the percent of cells showing apoptotic morphology and percent specific DNA fragmentation was observed, suggesting that physical exercise increased the incidence of apoptosis in tumor cells. Moreover, macrophages obtained from tumor-bearing mice, which underwent exercise training, showed an augmented tumoricidal activity and production of tumoricidal molecules like interleukin-1 (IL-1), tumor necrosis factor (TNF) and nitric oxide (NO). On the basis of this study it is suggested that the regression of tumor growth consequent to physical exercise training of tumor bearing host, may be due to an exercise-dependent augmentation of macrophage tumoricidal functions. [Copyright &y& Elsevier]

Abstract: The present investigation was carried out to investigate gender dimorphism with respect to the progressive in vivo growth a of T cell lymphoma in a murine system. It was observed that in vivo progression of a transplantable T cell lymphoma of spontaneous origin, designated as Dalton''s lymphoma (DL), shows differential growth kinetics in male and female mice. DL growth was observed to be faster in female mice as compared to male mice. We demonstrate the involvement of gender specific gonadal hormones, tumor-associated macrophage (TAM)-derived IL-1 and differential level of IL-4, IL-10 and TNF-α in the ascitic fluid of DL-bearing male and female mice. The study has a clinical significance, as the results will help in understanding the mechanism of gender dimorphism with respect to the progression of T cell tumors and in the designing of immunotherapy for such tumors. [Copyright &y& Elsevier]

The baculovirus protein P35 inhibits apoptosis in a diverse range of animals such as insects, nematodes and mammals. Evidence suggests that P35 can inhibit members of caspase family proteases that are key mediators of mammalian apoptosis. We demonstrate that p35 inhibits activation-induced nitric oxide (NO)-mediated apoptosis in the RAW 264.7 mouse macrophages. Parent or vector-transfected RAW 264.7 cells underwent apoptosis when treated with a combination of cisplatin and interferon-γ (IFN-γ) or LPS and IFN-γ in a NO-dependent manner. By contrast, RAW 264.7 cells stably expressing P35 did not undergo apoptosis when treated with a combination of cisplatin and IFN-γ or LPS and IFN-γ. Activation of parent, vector- or p35. transfected cells with cisplatin and IFN-γ or LPS and IFNy caused equivalent levels of inducible nitric oxide synthase (iNOS) expression and produced equal amounts of nitrite, which ruled out attenuated iNOS activity during P35 mediated protection. Rather, expression of P35 inhibited translocation of mitochondrial cytochrome c into cytosol, mitochondrial depolarization, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). These findings indicate that P35 inhibits NO induced apoptotic cell death of activated macrophages by inhibiting mitochondrial cytochrome c release, which suggests that P35 has targets upstream of the caspase cascade in apoptosis. [ABSTRACT FROM AUTHOR]

Mixed-ligand complexes of Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) with 5-fluorocytosine (5FC) and guanine (G) have been prepared in aqueous ethanol solution at pH of about 7. The prepared complexes were characterized by various physico-chemical methods viz. elemental analyses, infrared, UV-visible, magnetic measurements, and powder x-ray pattern. On the basis of IR studies, it is suggested that G acts as bidentate ligand coordinating through the N3 and N7 nitrogens whereas 5FC behaves as a monodentate and coordinates to the metal ions through the carbonyl oxygen only. These complexes were subjected to a screening system of Dalton's lymphoma (DL) tumor cells both in vivo and in vitro. Some complexes exhibit significant antitumor activity both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

A new ligand N-salicyloyl-N′-o-hydroxythiobenzhydrazide (H2Sotbh) forms complexes [Mn(HSotbh)2], [Fe(Sotbh-H)(H2O)2], [M(Sotbh)] [M=Co(II), Cu(II) and Zn(II)] and [Ni(Sotbh)(H2O)2], which were characterized by various physico-chemical techniques. Mo¨ssbauer spectrum of [Fe(Sotbh-H)(H2O)2] reveals the quantum admixture of 5/2 and 3/2 spin-states. Mn(II), Cu(II) and Ni(II) complexes were observed to inhibit the growth of tumor in vitro, whereas, Fe(III), Co(II), Zn(II) complexes did not. In vivo administration of Mn(II), Cu(II) and Ni(II) resulted in prolongation of survival of tumor bearing mice. Tumor bearing mice administered with Mn(II), Cu(II) and Ni(II) complexes showed reversal of tumor growth associated induction of apoptosis in lymphocytes. The paper discusses the possible mechanisms and therapeutic implication of the H2Sotbh and its metal complexes in tumor regression and tumor growth associated immunosuppression. [Copyright &y& Elsevier]

Tumor growth and its chemotherapeutic regimens manifest myelosuppression, which is one of the possible causes underlying the limited success of immunotherapeutic anticancer strategies. Hence, approaches are being designed to develop safer therapeutic regimens that may have minimal damaging action on the process of myelopoiesis. 3-Bromopyruvate (3-BP) is a highly potent antimetabolic agent displaying a broad spectrum antineoplastic activity. However, 3-BP has not been investigated for its effect on the process of myelopoiesis in a tumor-bearing host. Hence, in this investigation, we studied the myelopoietic effect of in vivo administration of 3-BP to a murine host bearing a progressively growing ascitic thymoma designated as Dalton's lymphoma (DL). 3-BP administration to the DL-bearing mice resulted in a myelopotentiating action, reflected by an elevated count of bone marrow cells (BMC) accompanied by augmented proliferative ability and a declined induction of apoptosis. The BMC of 3-BP-administered mice displayed enhanced responsiveness to macrophage colony-stimulating factor for colony-forming ability of myeloid lineage along with an enhanced differentiation of F4/80+ bone marrow-derived macrophages (BMDM). BMDM differentiated from the BMC of 3-BP-administered DL-bearing mice showed an augmented response to lipopolysaccharide and interferon-γ for activation, displaying an augmented tumor cytotoxicity, expression of cytokines, reactive oxygen species, nitric oxide, CD11c, TLR-4, and HSP70. These features are indicative of the differentiation of M1 subtype of macrophages. Thus, this study demonstrates the myelopotentiating action of 3-BP, indicating its hematopoietic safety and potential for reinforcing the differentiation of macrophages in a tumor-bearing host. [ABSTRACT FROM AUTHOR]

Highlights • Tumor cells display augmented inflammation & reprogrammed metabolism. • Diclofenac is a potent NSAID which inhibit tumor metabolism. • Molecular docking analysis revealed multiple targets of diclofenac. • Docking targets included molecules regulating tumor metabolism. • Diclofenac possesses potential for anticancer therapeutics. Abstract Diclofenac is a potent NSAID of clinical choice, which is widely used for containing inflammation. Moreover, recent experimental evidences overwhelmingly substantiate its antineoplastic potential. However, the precise molecular mechanisms of diclofenac's anticancer activity remain poorly understood. Neoplastic cells display reprogrammed metabolic features, which are manifested and regulated by a complex networking of molecular pathways. However, the effect of diclofenac on tumor cell metabolism are not yet clearly deciphered. Hence, the present investigation was carried out to identify and characterize key diclofenac targets of tumor metabolism, cell survival and chemoresistance. The interactions of diclofenac with such targets was analysed by PatchDock and YASARA (Yet Another Scientific Artificial Reality Application). The docking ability of diclofenac with its targets was based on analysis of dissociation constant (Kd), geometric shape complementarity score (GSC score), approximate interface area (AI area) and binding energy. The findings of this investigation reveal that diclofenac is capable of interacting with all of the selected molecular targets. Prominent interactions were observed with GLUT1, MCT4, LDH A, COX1, COX2, BCRP/ABCG2, HDM2/MDM2 and MRP1 compared to other targets. Interactions were of noncovalent nature involving ionic, hydrophobic interactions, Van der Waals forces and H-bonds, which varied depending on targets. This study for the first time, characterizes the nature of molecular interactions of diclofenac with selected targets involved in cancer cell metabolism, pH homeostasis, chemosensitivity, cell signalling and inflammation. Hence, these findings will be highly beneficial in optimizing the utility of diclofenac in development of novel cancer therapeutics. Graphical abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]

Abstract Neoplastic cells display altered biosynthetic and bioenergetic machinery to support cell survival. Therefore, cancer cells optimally utilize all available fuel resources to pump their highly upregulated metabolic pathways. While glucose is the main carbon source, transformed cells also utilize other molecules, which can be utilized in metabolic pathways, designated as alternative fuels. Acetate is one of such alternative metabolic fuels, which is mainly consumed in carbohydrate and lipid metabolism. However, studies demonstrate the contradictory effects of acetate on tumor cell survival. Moreover, the mechanisms of its antitumor actions remain poorly understood. Further, the spectrum of acetate susceptible tumor targets needs to be characterized in order to optimize the use of acetate in maneuvering tumor progression as a therapeutic strategy. As the effect of acetate on survival properties of the tumor cells of thymic origin is not worked out, in the present study the effect of acetate was investigated against tumor cells derived from a murine thymoma designated as Dalton's Lymphoma (DL). Acetate treatment of tumor cells inhibited tumor cell survival accompanied by induction of apoptotic cell death, associated with modulated expression of cell survival regulatory HIF1α, ROS, p53, Caspase 3, Bax and HSP70 along with the elevated level of cytosolic cytochrome c. Acetate treatment also modulated the expression of pH regulators MCT-1 and V-ATPase accompanied by altered pH homeostasis. Expression of MDR and lipid metabolism regulatory molecules was also inhibited in tumor cells upon acetate exposure. Further, pre-exposure of tumor cells to α-CHC (α-cyano-4-hydroxycinnamate), an inhibitor of MCT-1, partially abrogated the cytotoxic action of acetate. These findings shed a new light regarding the effect and mechanisms of the exogenous acetate on the biology of tumor cells of thymic origin. Highlights • In vitro exposure of tumor cells to acetate causes metabolic inhibition • Acetate treatment triggers induction of apoptosis • Acetate exposed tumor cells show modulated cell survival regulation • Acetate exposure interferes with pH homeostasis [ABSTRACT FROM AUTHOR]

Abstract Acetate is a short chain fatty acid, comprising carbon, hydrogen and oxygen (C 2 H 3 O 2 −), which has emerged as a key alternative fuel for cellular metabolism. Beginning its voyage from the abiotic atmosphere, acetate has contributed to the physiology of both prokaryotes and eukaryotes. The main role of acetate includes its contribution to the global carbon cycle, bioenergetic and biosynthetic metabolic processes. Based on the ability to produce and consume acetate, organisms are categorized as acetogenic, acetate-consumers or both depending on their genetic make-up of the metabolizing enzymes' repertoire. The key molecules implicated in utilization and production of acetate include, but not limited to, monocarboxylate transporters, enzymes regulating acetate utilization like AMP-forming Acetyl CoA synthetase (ACS-AMP), Acyl-CoA short chain synthetase 1, 2 (ACSS1, 2), and production like Acetate kinase (ACK)/Phosphotransacetylase (PTA), ADP-forming acetyl CoA synthetase (ACS-ADP), Pyruvate:ferredoxin oxidoreductase, histone deacetylase and acetyl CoA hydrolase. These enzymes are utilized by the acetate homeostasis machinery in a variable manner. As malignant cells also display highly upregulated metabolic processes for rapid energy generation, they display an immense need for alternative carbon sources to fuel their metabolism. Tumor cells display over expression of transporters and enzymes implicated in their acetate utility machinery. This review also highlights mechanisms of the pro and antitumor potential of acetate depending on the genetic and metabolic makeup of neoplastic cells. The present review is a comprehensive compilation of the available literature with respect to the role of acetate in the biology of living organisms and its potential for being maneuvered in anticancer therapeutics. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. [ABSTRACT FROM AUTHOR]

3-Bromopyruvate (3-BP), brominated derivative of pyruvate, possesses strong antitumor potential, owing to its ability to inhibit multiple target molecules crucial for survival of neoplastic cells. Although, 3-BP displays cytotoxicity against a wide variety of tumors, there is no report with respect to malignancies of thymic origin. Therefore, we investigated its antineoplastic action in vitro against tumor cells of a murine transplantable lymphoma of thymoma origin, designated as Dalton's lymphoma (DL). 3-BP treatment of tumor cells inhibited metabolism and survival with augmented induction of apoptosis and necrosis. 3-BP treatment suppressed lactate release, glucose uptake, deregulated pH homeostasis and augmented chemosensitization. It also altered expression of metabolism, chemosensitivity and cell survival regulatory molecules including HK 2, GAPDH, LDH, SDH, HIF-1α, MDR-1 & GLUT-1 and cytokine repertoire of IFN-γ, IL-6, IL-10, & VEGF. Pretreatment with MCT-1 inhibitor α-cyano-4-hydroxycinnamate and siRNA gene silencing of HK 2 implicated the role of MCT-1 and HK 2 in 3-BP cytotoxicity. 3-BP also altered expression of cell death regulatory Bcl-2, Mcl-1, caspase-3 accompanied by increased cytochrome c release, indicating mitochondrial mode of cell death. The study collates possible molecular mechanisms of cytotoxic action of 3-BP, which will help to optimize the therapeutic efficacy of 3-BP against tumors of thymic origin. [ABSTRACT FROM AUTHOR]

Altered metabolism is an emerging hallmark of cancer, as malignant cells display a mammoth up-regulation of enzymes responsible for steering their bioenergetic and biosynthetic machinery. Thus, the recent anticancer therapeutic strategies focus on the targeting of metabolic enzymes, which has led to the identification of specific metabolic inhibitors. One of such inhibitors is 3-bromopyruvate (3-BP), with broad spectrum of anticancer activity due to its ability to inhibit multiple metabolic enzymes. However, the molecular characterization of its binding to the wide spectrum of target enzymes remains largely elusive. Therefore, in the present study we undertook in silico investigations to decipher the molecular nature of the docking of 3-BP with key target enzymes of glycolysis and TCA cycle by PatchDock and YASARA docking tools. Additionally, derivatives of 3-BP, dibromopyruvate (DBPA) and propionic acid (PA), with reported biological activity, were also investigated for docking to important target metabolic enzymes of 3-BP, in order to predict their therapeutic efficacy versus that of 3-BP. A comparison of the docking scores with respect to 3-BP indicated that both of these derivatives display a better binding strength to metabolic enzymes. Further, analysis of the drug likeness of 3-BP, DBPA and PA by Lipinski filter, admetSAR and FAF Drug3 indicated that all of these agents showed desirable drug-like criteria. The outcome of this investigation sheds light on the molecular characteristics of the binding of 3-BP and its derivatives with metabolic enzymes and thus may significantly contribute in designing and optimizing therapeutic strategies against cancer by using these agents. [ABSTRACT FROM AUTHOR]

Prior studies established constitutively active AP-1, NF- κB, and STAT3 signaling in oral cancer. Differential expression/activation of specific members of these transcription factors has been documented in HPV-positive oral lesions that respond better to therapy. We performed a comprehensive analysis of differentially expressed, transcriptionally active members of these pivotal signaling mediators to develop specific signatures of HPV-positive and HPV-negative oral lesions by immunohistochemical method that is applicable in low-resource settings. We examined a total of 31 prospective and 30 formalin-fixed, paraffin-embedded tissues from treatment-naïve, histopathologically and clinically confirmed cases diagnosed as oral or oropharyngeal squamous cell carcinoma ( OSCC/ OPSCC). Following determination of their HPV status by GP5 + / GP6 + PCR, the sequential sections of the tissues were evaluated for expression of JunB, JunD, c-Fos, p50, p65, STAT3, and pSTAT3(Y705), along with two key regulatory proteins pEGFR and p16 by IHC. Independent analysis of JunB and p65 showed direct correlation with HPV positivity, whereas STAT3 and pSTAT3 were inversely correlated. A combined analysis of transcription factors revealed a more restrictive combination, characterized by the presence of AP-1 and NF- κB lacking involvement of STAT3 that strongly correlated with HPV-positive tumors. Presence of STAT3/ pSTAT3 with NF- κB irrespective of the presence or absence of AP-1 members was present in HPV-negative lesions. Expression of pSTAT3 strongly correlated with all the AP-1/ NF- κB members (except JunD), its upstream activator pEGFRY1092, and HPV infection-related negative regulator p16. Overall, we show a simple combination of AP-1, NF- κB, and STAT3 members' expression that may serve as molecular signature of HPV-positive lesions or more broadly the tumors that show better prognosis. [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: The present investigation was undertaken to study if curcumin, which is recognized for its potential as an antineoplastic and immunopotentiating agent, can also influence the process of myelopoiesis in a tumor-bearing host. Administration of curcumin to tumor-bearing host augmented count of bone marrow cell (BMC) accompanied by an up-regulated BMC survival and a declined induction of apoptosis. Curcumin administration modulated expression of cell survival regulatory molecules: Bcl2, p53, caspase-activated DNase (CAD) and p53-upregulated modulator of apoptosis (PUMA) along with enhanced expression of genes of receptors for M-CSF and GM-CSF in BMC. The BMC harvested from curcumin-administered hosts showed an up-regulated colony forming ability with predominant differentiation into bone marrow-derived macrophages (BMDM), responsive for activation to tumoricidal state. The number of F4/80 positive bone marrow resident macrophages (BMM), showing an augmented expression of M-CSF, was also augmented in the bone marrow of curcumin-administered host. In vitro reconstitution experiments indicated that only BMM of curcumin-administered hosts, but not in vitro curcumin-exposed BMM, augmented BMC survival. It suggests that curcumin-dependent modulation of BMM is of indirect nature. Such prosurvival action of curcumin is associated with altered TH1/TH2 cytokine balance in serum. Augmented level of serum-borne IFN-γ was found to mediate modulation of BMM to produce enhanced amount of monokines (IL-1, IL-6, TNF-α), which are suggested to augment the BMC survival. Taken together the present investigation indicates that curcumin can potentiate myelopoiesis in a tumor-bearing host, which may have implications in its therapeutic utility. [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]

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]

Recently, we reported that treadmill exercise renders survival benefits in a murine tumor model of a transplantable lymphoma of spontaneous origin, designated as Dalton’s lymphoma (DL), owing to an augmented apoptosis of tumor cells. However, the underlying the mechanisms of the same remained unclear with respect to the role alterations if any in the components of tumor microenvironment following physical exercise. Therefore, in the present we investigated the role of oxygen, pH, lactate and cytokines of tumor micro-environment associated with physical exercise-dependent alteration in the growth properties of tumor cells to explore their contribution in modulation of tumor. Physical exercise of tumor-bearing host resulted in a decreased angiogenesis in the vicinity of tumor. This was also found to be accompanied by a decrease in erythrocyte count and increase in the level of oxygen while the content of lactate showed a concomitant decrease in the tumor microenvironment along with normalization of pH. Moreover, physical exercise also resulted in an inhibition of VEGF expression which was correlated to an altered expression of cytokines: IL-1, IL-4, IL-10, TGF-β and IFN-γ. Ascitic fluid of tumor-bearing host subjected to physical exercise showed an increase in nitric oxide content along with an increase in the expression of inducible nitric oxide synthase (iNOS). The study discusses the possible role of the aforesaid alterations in constituents of tumor microenvironment of tumor-bearing host following physical exercise in retardation of tumor growth. [ABSTRACT FROM AUTHOR]

It is well established that the immune potential declines with age. However, there is a great paucity of information regarding role of monocytes in elderly suffering from cerebrovascular accident. This present study was undertaken to investigate if the functions of peripheral blood mononuclear cells have any correlation to the manifestation of an age-associated cerebrovascular disorders: myocardial infraction, cerebrovascular (infract & hemorrhage). An age-associated inhibition in the production of interleukin-1 (IL-1) by monocytes was observed while the production of nitric oxide (NO) remained unaltered in the response of monocytes, obtained from normal elderly donors, to Lipopolysaccharide (LPS) treatment in vitro. Cerebrovascular pathologies were found to be associated with an augmentation of IL-1 production by monocyte, while NO production was augmented in case of CVA (hemorrhage) and MI. Trace element copper was found to be lower in the serum of patients suffering from CVA, while concentration of zinc was found to be elevated in serum compared to these trace elements in normal adults. Thus these factors are likely to play a role in the pathogenesis of age-related cerebrovascular disorders. [ABSTRACT FROM AUTHOR]

Mixed-ligand complexes of Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) with adenine as primary ligand and 5-bromouracil as secondary ligand were prepared in aqueous ethanol solution at pH of about 7 and subjected to a screening system of Dalton's Lymphoma (DL) tumor cells in vitro for the evaluation of viability, 3H-thymidine incorporation and induction of apoptosis in tumor cells. The isolated complexes were characterized by various physico-chemical methods. Solution studies were performed pH-metrically for the interaction of the above metal ions with adenine and 5-bromouracil separately (binary) and in the presence of each other (ternary) at 25±0.1 °C temperature and a constant ionic strength of 0.1 M NaNO3 in aqueous solution. [ABSTRACT FROM AUTHOR]