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Bicarbonate transporter (BCT) plays a crucial role in maintaining pH homeostasis of tumor cells by import of HCO3(-). This helps the tumor cells in manifesting extracellular tumor acidosis, accompanied by a relative intracellular alkalinization, which in turn promotes tumor progression. Therefore, blocking BCT-mediated HCO3(-) transport is envisaged as a promising anticancer therapeutic approach. Thus, using a murine model of a T cell lymphoma, designated as Dalton's lymphoma (DL), in the present in vitro investigation the antitumor consequences of blocking BCT function by its inhibitor 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate (SITS) were explored. Treatment of DL cells with SITS resulted in an increase in the extracellular pH, associated with a decline in DL cell survival and augmented induction of apoptosis. BCT inhibition also elevated the expression of cytochrome c, caspase-9, caspase-3, Bax, reactive oxygen species, and nitric oxide along with inhibition of HSP-70 and Bcl2, which regulate tumor cell survival and apoptosis. SITS-treated DL cells displayed upregulated production of IFN-γ and IL-6 along with a decline of IL-10. Treatment of DL cells with SITS also inhibited the expression of fatty acid synthase, which is crucial for membrane biogenesis in neoplastic cells. The expression of lactate transporter MCT-1 and multidrug resistance regulating protein MRP-1 got inhibited along with hampered uptake of glucose and lactate production in SITS-treated DL cells. Thus, the declined tumor cell survival following inhibition of BCT could be the consequence of interplay of several inter-connected regulatory molecular events. The outcome of this study indicates the potential of BCT inhibition as a novel therapeutic approach for treatment of hematological malignancies.

The present investigation was undertaken to study the effect of in vitro exposure of Colo205, colonadenocarcinoma cells, to monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamate (αCHC) on cell survival and evolution of resistance to chemotherapeutic drug cisplatin. αCHC-treated Colo205 cells showed inhibition of survival accompanied by an augmented induction of apoptosis. Changes in cell survival properties were associated with alterations in lactate efflux, pH homeostasis, expression of glucose transporters, glucose uptake, HIF-1α, generation of nitric oxide, expression pattern of some key cell survival regulatory molecules: Bcl2, Bax, active caspase-3 and p53. Pretreatment of Colo205 cells with αCHC also altered their susceptibility to the cytotoxicity of cisplatin accompanied by altered expression of multidrug resistance regulating MDR1 and MRP1 genes. This study for the first time deciphers some of the key molecular events underlying modulation of cell survival of cancer cells of colorectal origin by αCHC and its contribution to chemosensitization against cisplatin. Thus these findings will be of immense help in further research for optimizing the use of αCHC for improving the chemotherapeutic efficacy of anticancer drugs like cisplatin.

In the present investigation, we explored the molecular mechanisms of the tumoricidal action of α-cyano-4-hydroxycinnamate (αCHC) on the cells of Dalton's lymphoma (DL), which is a murine T cell lymphoma. In-vitro treatment of the DL cells with αCHC resulted in the modulation of the biophysical parameters of the tumor cell culture medium with respect to pH, nitric oxide, glucose, and lactate, accompanied by an alteration in the expression of cytokines (IL-10, IL-6, and IFN-γ) and cell survival-regulatory proteins such as Bcl2, p53, caspase-3, caspase-activated DNase, HSP70, and IL2R. The expression of the pH-regulatory proteins vacuolar ATPase and MCT1 was also found to be altered. The study discusses the possible role of the aforementioned alterations triggered by αCHC in the induction of tumor cell apoptosis and decreased cell survival. These findings will provide a new insight into the novel molecular mechanisms of the antitumor action of αCHC.

The present study was conducted to investigate if anti-inflammatory drug aspirin could alter the cytotoxic action of cisplatin on tumor cells. Using a transplantable T cell lymphoma in a murine model, we demonstrate that exposure to aspirin exerts a priming action on tumor cells, rendering them susceptible to induction of cell death by cisplatin with consequences on retardation of tumor progression. The priming action of aspirin on tumor cells was found to be dependent on an altered constitution of tumor microenvironment with respect to decline of acidosis and modulation in the expression of cell cycle and survival regulatory molecules like cyclin B1, cyclin D, bcl-2, bcl-xL, p53, and cytokines: IL-4, IL-10, IFN- γ & VEGF. The study also discusses possible mechanisms underlying augmentary action of aspirin on cisplatin-mediated tumor cells killing. This is the first report showing that pre-exposure of tumor cells to aspirin lowers the concentration of cisplatin to exert its cytotoxic action. The finding of this study will help in designing novel antitumor protocols with reduced dose of cisplatin.

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 © 2012 Elsevier B.V. All rights reserved.)

The present investigation was undertaken to study if a gender-dependent differential induction of tumor cell apoptosis is responsible for the manifestation of gender dimorphism observed in the growth of a transplantable murine T cell lymphoma, designated as Dalton's lymphoma (DL). Tumor cell samples obtained from male tumor-bearing mice showed a higher number of cells with apoptotic morphology compared to that observed in female tumor-bearing mice. In this report we demonstrate that male hormone androgen and female hormone estrogen can differentially modulate tumor cell proliferation and apoptosis through alteration in the expression pattern of cell death regulating genes: p53 and CAD. DL cells were shown to express mRNA for androgen and estrogen receptors. Further these gonadal hormones also induced tumor cells to produce tumor growth regulating proteins: VEGF, TGF-beta, IL-2, IL-2R, SOCS, Hsp-70 and IFN-gamma which in turn either through autocrine action on tumor cells or via TAM-derived NO were observed to regulate tumor cell apoptosis leading to gender dimorphism of tumor growth. This study also discusses the possible mechanism involved. The study has clinical significance as these results will helps in understanding the mechanism of gender dimorphism with respect to the progression of T-cells tumors.

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-gamma (IFN-gamma) or LPS and IFN-gamma 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-gamma or LPS and IFN-gamma. Activation of parent, vector- or p35-transfected cells with cisplatin and IFN-gamma or LPS and IFN-gamma 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.

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: 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]

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]

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]

It has been observed that the progressive ascitic growth of a transplantable T cell lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), induces inhibition of various immune responses and is associated with an involution of the thymus accompanied by a massive depletion of the cortical region and alteration in the distribution of thymocytes, with a decrease in CD4+CD8+, CD4+CD8- and CD4-CD8+ thymocytes. Morphological evaluation of thymocytes from DL-bearing mice revealed that with the progression of DL, a majority of thymocytes exhibited morphological features characteristic of apoptotic cell death, which included contracted cell bodies, condensed, uniformly circumscribed and densely stained chromatin, and membrane-bound apoptotic bodies containing one or more nuclear fragments. Quantitative and qualitative analysis of the DNA extracted from the thymocytes of DL-bearing mice revealed DNA fragmentation that increased concomitantly with the progression of DL and showed an oligonucleosomal DNA ladder pattern upon agarose gel electrophoresis, a hallmark of apoptotic cell death. Attempts to identify apoptotic factor(s) showed that the serum of DL-bearing mice contained certain soluble factor(s) that augmented the induction of apoptotis in thymocytes in a time- and dose-dependent manner. Although DL cells or their products, such as DL-cell-conditioned medium or DL-cell-free ascitic fluid, could also induce apoptosis of thymocytes in vitro, the magnitude of the same was consistently lower than that induced by the serum of DL-bearing mice. Further, elucidation of the mechanism of apoptosis induction in thymocytes with respect to the involvement of apoptosis-related genes revealed that the death pathway followed an interleukin-1 β-converting-enzyme-dependent, Fas-mediated apoptotic cascade, with a concomitant increase in the protein products of the bax, bad, p53, fas and fasL genes and cleavage of the 23-kD N-terminal fragment of Bcl-2 that exhibited Bax-like death effector properties. Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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: 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: 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: 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]

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]

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]