Necrotic Activity Research Articles

The Molecular Mechanisms of Apoptosis Induced by A llium flavum L. and Synergistic Effects with New-Synthesized Pd(II) Complex on Colon Cancer Cells

Considering that induction of apoptosis is one of the main strategies in cancer therapy, the molecular mechanisms of cytotoxic effects of Allium flavum L. on colon cancer cell lines were investigated and applied in single and co-treatments with new-synthesized Pd(II) complex. The analysis of chemical composition identified caffeic acid glycosides as the most dominant phenolics in A. flavum extract. In all investigated extracts, A. flavum showed cytotoxic effects on colon cancer cells (IC50 = 1.64–84 μg/mL) but not on healthy cells. Combinations of plant extracts with Pd(II) complex caused lower IC50 values and better proapoptotic activity. Pd(II) complex induced high percentage of necrosis in a single treatment, but in the combination with plant extracts it had better proapoptotic and lower necrotic activity. Treatments and co-treatments induced higher O2− production and influenced apoptosis biomarkers, leading to Fas protein overexpression and activation of caspases 8 and 9. Practical Applications In view of the achieved anticancer properties, insufficiently investigated Allium flavum L. is a promising candidate for developing new anticancer compounds and deserves further research and scientific validation. This study has great impact on investigation of new anticancer substances from natural source, focuses on the importance of using plants as the source of medicinal drugs, contributes to the development of the appropriate therapy and gives contribution in both scientific and practical means. Because of its synergistic actions with the newly synthesized chemical anticancer agent and ability to reduce side effects (thus reducing necrotic activity of Pd[II] complex), A. flavum can be used as a dietary food supplement or supplement to chemotherapy perhaps in combination with currently used chemotherapeutics or in some strategies in cancer therapy. This finding is also important from a nutritional point of view because this extracts contain significant amounts of bioactive constituents, which provide health benefits.

The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

The cytotoxicity of mitragynine, the dominant alkaloid of the narcotic-like herb,Mitragyna speciosaKorth (Kratom) involves cell cycle arrest, apoptosis and opiate receptors.

The xylanase inhibitor TAXI-III counteracts the necrotic activity of a Fusarium graminearum xylanase in vitro and in durum wheat transgenic plants.

The xylanase inhibitor TAXI-III has been proven to delay Fusarium head blight (FHB) symptoms caused by Fusarium graminearum in transgenic durum wheat plants. To elucidate the molecular mechanism underlying the capacity of the TAXI-III transgenic plants to limit FHB symptoms, we treated wheat tissues with the xylanase FGSG_03624, hitherto shown to induce cell death and hydrogen peroxide accumulation. Experiments performed on lemmas of flowering wheat spikes and wheat cell suspension cultures demonstrated that pre-incubation of xylanase FGSG_03624 with TAXI-III significantly decreased cell death. Most interestingly, a reduced cell death relative to control non-transgenic plants was also obtained by treating, with the same xylanase, lemmas of TAXI-III transgenic plants. Molecular modelling studies predicted an interaction between the TAXI-III residue H395 and residues E122 and E214 belonging to the active site of xylanase FGSG_03624. These results provide, for the first time, clear indications in vitro and in planta that a xylanase inhibitor can prevent the necrotic activity of a xylanase, and suggest that the reduced FHB symptoms on transgenic TAXI-III plants may be a result not only of the direct inhibition of xylanase activity secreted by the pathogen, but also of the capacity of TAXI-III to avoid host cell death.

Measurement of Apoptotic and Necrotic Cell Death in Primary Hepatocyte Cultures.

Hepatotoxicity, including drug-induced liver injury, is frequently accompanied by cell death. The latter is typically driven by apoptosis or necrosis, which substantially differ based upon biochemical and morphological criteria. This chapter describes two commonly used methods to probe apoptotic and necrotic activities in adherent monolayer cultures of primary hepatocytes. The apoptosis assay uses a prototypical substrate of caspase 3, the main executor of apoptotic cell death, which can be cleaved, yielding a product that can be measured fluorimetrically. The second assay relies on the disruption of the cell plasma membrane, which typically occurs in necrotic cell death and that results in the extracellular release of cytoplasmic enzymes, such as lactate dehydrogenase. The latter can be indirectly assessed by spectrophotometrically measuring the consumption of reduced nicotinamide adenine dinucleotide.

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

Multiple Organ Failure Syndrome In Patients With Acute Diffuse Peritonitis

The results of the surgical treatment of 123 patients with acute diffuse peritonitis have been analyzed. The dynamics of necrotic processes activity in the mucous membrane of the small intestine according to its affection marker I-FABP, the liver – LFABP and of the heart – H-FABP in preoperative period and on 1, 3, 5, 7 day after the operation. Due to the level of multiple organ failure according to G.R. Bernard et al. scale (1995) and the level of bacterial contamination of the abdominal cavity during the operative treatment of patients with acute diffuse peritonitis, the choice of the method (closed and open) of intestinal intubation, programmed laparostomia is indicated. The methods of pharmacological (inotropic, antibacterial, infusion) correction of multiple organ failure syndrome during a comprehensive treatment of patients in toxic and terminal stages of acute diffuse peritonitis are worked out enabling to reduce the frequency of post-operational complications from 73,6% to 39,1%, and to reduce the level of post-operational lethal outcome from 14,1% to 8,5%.

Seed Dormancy Breaking Diterpenoids, Including Novel Brassicicenes J and K, from Fungus Alternaria brassicicola, and their Necrotic/Apoptotic Activities in HL-60 Cells

To find new metabolites similar to cotylenins and fusicoccins from the fungus Alternaria brassicicola, screening tests were carried out using the lettuce seed dormancy breaking assay. Activity-guided fractionation of the EtOAc extract from the culture using the assay afforded the isolation of two novel fusicoccane diterpenoids named brassicicenes J (1) and K (2), along with three known brassicicenes A (3), B (4), and F (5). Their structures were elucidated from extensive NMR spectral data and by comparison of these with those reported in the literature. Brassicicenes (1-5) exhibited weak to moderate seed dormancy breaking activities against lettuce seeds in the presence of abscisic acid. In addition, the necrotic/apoptotic activities of the brassicicenes (1-5), fusicoccin A (6) and cotylenin A (7) were evaluated by determining their cytotoxicity, cell viability and caspase-3/7 activation on the HL-60 cell line. Brassicicene K (2) exhibited similar cytostatic profiles to that of cotylenin A (7), and brassicicenes J (1), A (3), B (4), and F (5) exhibited necrotic activity. This is the first report of the seed dormancy breaking activity of brassicicenes in plants, and of necrotic/apoptotic activity in mammalian cells.

XaxAB-like binary toxin fromPhotorhabdus luminescensexhibits both insecticidal activity and cytotoxicity

The enterobacterium Photorhabdus luminescens produces a number of toxins to kill its insect host. By analyzing the genomic sequence of P.luminescens TT01, we found that amino acid sequences encoded by plu1961 and plu1962 showed high similarity to XaxAB binary toxin of Xenorhabuds nematophila, which has both necrotic and apoptotic activities in both insect and mammalian cells in vitro. To evaluate the biological activity of Plu1961/Plu1962, their coding genes were cloned and expressed in Escherichia coli. Both Plu1961 and Plu1962 were expressed as soluble protein in BL21 (DE3) and their mixture caused insect midgut CF-203 cells death via necrosis. Confocal fluorescence microscopy showed that Plu1961/Plu1962 mixture was able to depolymerize microtubule and induce the increase in plasma membrane permeabilization in CF-203 cells. Moreover, co-expression of Plu1961/Plu1962 in the same cytoplasm exhibited cytotoxic effect against mammalian cells (B16, 4T1, and HeLa cells) and injectable activity against Spodoptera exigua larvae. Until now, two types of binary toxins have been identified in P.luminescens, the first type is PirAB and Plu1961/Plu1962 is the second one. The biological role of Plu1961/Plu1962 binary toxin played in the infection process should attract more attention in future.

Hepatoprotective action of dietary bluefin tuna skin proteins on CCl4-intoxicated mice

We have shown that dietary bluefin tuna skin (TUS) protects against carbon tetrachloride (CCl4)-induced hepatic damage in mice. The CCl4-induced necrotic area was decreased in mice fed a TUS-containing diet. Consistent with the decreased necrotic area, dietary TUS markedly lowered the elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the thiobarbituric acid-reactive substance (TBARS) formation induced by CCl4 injection. TUS diets also decreased phosphorylation of inhibitory kappa B-α and blocked the translocation of nuclear factor-kappa B to the nucleus. TUS is composed mainly (80.7 %) of type I collagen, and our results revealed that dietary tuna collagen peptides (TUCP) attenuated the increased hepatic necrotic area, serum AST and ALT activities, and liver TBARS levels induced by CCl4, similar to TUS, thus enabling us to attribute the hepatoprotective action of TUS in CCl4-intoxicated mice to tuna collagen. Therefore, TUS and TUCP may be potential food resources that are capable of alleviating hepatitis symptoms.

New findings on Simalikalactone D, an antimalarial compound from Quassia amara L. (Simaroubaceae)

Quassia amara L. (Simaroubaceae) is a species widely used as tonic and is claimed to be an efficient antimalarial all over the Northern part of the Amazon basin. Quassinoid compound Simalikalactone D (SkD) has been shown to be one of the molecules responsible for the antiplasmodial activity of a watery preparation made out of juvenile fresh leaves of this plant. Because of its strong antimalarial activity, we decided to have a further insight of SkD pharmacological properties, alone or in association with classical antimalarials. At concentrations of up to 200μM, we showed herein that SkD did not exert any apoptotic or necrotic activities in vitro on lymphoblastic cells. However, an antiproliferative effect was evident at concentrations higher than 45nM. SkD was inefficient at inhibiting heme biomineralization and the new permeability pathways induced by the parasite in the host erythrocyte membrane. With respect to Plasmodium falciparum erythrocytic stages, SkD was almost inactive on earlier and later parasite stages, but potently active at the 30th h of parasite cycle when DNA replicates in mature trophozoites. In vitro combination studies with conventional antimalarial drugs showed that SkD synergizes with atovaquone (ATO). The activity of ATO on the Plasmodium mitochondrial membrane potential was enhanced by SkD, which on its own had a poor effect on this cellular parameter.

S24 * S-ADENOSYLMETHIONINE IN THE PATHOGENESIS AND TREATMENT OF ALCOHOLIC LIVER DISEASE * S24.1 * THE ROLE OF ALTERED SAME METABOLISM IN ALCOHOL-INDUCED ER STRESS AND LIVER INJURY

S24 * S-ADENOSYLMETHIONINE IN THE PATHOGENESIS AND TREATMENT OF ALCOHOLIC LIVER DISEASE * S24.1 * THE ROLE OF ALTERED SAME METABOLISM IN ALCOHOL-INDUCED ER STRESS AND LIVER INJURY

Characterization of spontaneous cell death in monolayer cultures of primary hepatocytes

Monolayer cultures of primary hepatocytes, isolated from freshly removed livers, represent widely used in vitro tools in the area of liver physiology and pathology, pharmacology and toxicology. However, a major shortcoming of these systems is that they cope with dedifferentiation, which is accompanied by spontaneous cell death. The goal of the present study was to elucidate the mechanisms that drive the process of self-generated cell demise in primary hepatocyte cultures. For this purpose, isolated rat hepatocytes were cultivated under conventional conditions, and the occurrence of apoptosis and necrosis was monitored during 4days by performing a set of acknowledged cell death assays. These included examination of cell morphology by light microscopy, quantification of apoptotic and necrotic cell populations by Hoechst 33342 and propidium iodide in situ staining, assessment of apoptotic and necrotic activities by measuring caspase 3-like activity and extracellular leakage of lactate dehydrogenase, and studying the expression of apoptosis regulators through immunoblot analysis. In essence, two cell death peaks were observed, namely shortly after cell seeding and in the final stages of the cultivation period, both involving apoptotic and necrotic actions. The outcome of this study not only sheds new light onto the molecular processes that underlie spontaneous cell death in primary hepatocyte cultures, but also opens perspectives for the establishment of strategies to increase cell survival in these popular in vitro systems.

Endobacteria in the tentacles of selected cnidarian species and in the cerata of their nudibranch predators

This is the first genetic analysis comparing cultured endobacteria discovered in the tentacles of cnidarian species (Tubularia indivisa, Tubularia larynx, Corymorpha nutans, Sagartia elegans) with those found in the cerata tips of selected nudibranch species (Berghia caerulescens, Coryphella lineata, Coryphella gracilis, Janolus cristatus, Polycera faeroensis, Polycera quadrilineata, Doto coronata, Dendronotus frondosus). Shared pathogenic activities were found among other microorganisms in the Pseudoalteromonas tetraodonis group (TTX), and the Vibrio splendidus group (haemolytic, septicaemic, necrotic activity). Specific autochthonous endobacteria of extremely low similarity to their next neighbours were detected in nudibranch cerata. These organisms are regarded as new and unknown endobacteria; among them were Pseudoalteromonas luteoviolacea (95%), Orientia tsutsugamushi (84%), Gracilimonas tropica (96%), Balneola alkaliphia (95%), Loktanella rosea (97%). SEM micrographs provide insight into endobacterial aggregates in cnidarian tentacles and nudibranch cerata. Since certain nudibranch predators prey on cnidarian species, it is assumed that cnidarian tentacle bacteria are directly transferred to nudibranch cerata. The pathogenic endobacteria may contribute to the chemical defence of both the nudibranch and cnidarian species investigated.

Enzymatic and toxinological activities of Hypnale hypnale (hump-nosed pit viper) venom and its fractionation by ion exchange high performance liquid chromatography

Hypnale hypnale (hump-nosed pit viper) has been recently identified as one of the medically important venomous snakes in Sri Lanka and on the southwestern coast of India. The characterization of its venom is essential for understanding the pathophysiology of envenomation and for optimizing its management. In the present study, the biological properties of Hypnale hypnale venom and venom fractions obtained using Resource Q ion exchange chromatography were determined. The venom exhibited toxic activities typical of pit viper venom, comparable to that of its sister taxon, the Malayan pit viper (Calloselasma rhodostoma). Particularly noteworthy were its high activities of thrombin-like enzyme, proteases, phospholipase A2, L-amino acid oxidase and hyaluronidase. The thrombin-like enzyme was mainly acidic and distributed over several chromatography fractions, indicating its existence in multiple isoforms. The hemorrhagic and necrotic activities of the venom were likely associated with the proteolytic enzyme found mainly in the basic fraction. Phospholipase A2 and phosphomonoesterase exist in both acidic and basic isoforms, while L-amino acid oxidase and hyaluronidase are highly acidic. The venom clotting activity on fibrinogens showed distinct species specificity in the following increasing order for clotting time: bovine < rabbit < goat < human < horse < < dog, and was comparable to that of C. rhodostoma venom. Its clot formation on human fibrinogen is gradual and prolonged, a phenomenon suggestive of consumptive coagulopathy as a complication observed clinically. At an intramuscular sublethal dose, the venom did not cause acute kidney injury in a rodent model, contrary to the positive control group treated with Daboia russelii venom. Nephrotoxicity may result from higher venom doses in the context of coagulopathy, as a complication provoked by venom hematoxicity.

Cross neutralization of Hypnale hypnale (hump-nosed pit viper) venom by polyvalent and monovalent Malayan pit viper antivenoms in vitro and in a rodent model

Hypnale hypnale (hump-nosed pit viper) is a medically important venomous snake in Sri Lanka and Southwestern India. Bite of this snake may result in hemostatic dysfunction, acute kidney injury and death. Clinical studies indicated that the locally available polyvalent antivenoms produced in India are not effective against hump-nosed pit viper envenoming. Hence, there is an urgent need to search for effective antivenom. In this paper, we examined the ability of Calloselasma rhodostoma (Malayan pit viper) monovalent antivenom and the Hemato polyvalent antivenom (both produced by Thai Red Cross Society, TRCS) to neutralize the lethality and toxic effects of H. hypnale venom, as C. rhodostoma is considered a sister taxon of H. hypnale. In vitro neutralization studies showed that the Hemato polyvalent antivenom effectively neutralized the lethality of H. hypnale venom (1.52mgvenom/mL antivenom) as well as the hemorrhagic, procoagulant and necrotic activities of the venom. The monovalent C. rhodostoma antivenom could also neutralize the lethality and toxic activities of the venom, but the potency was lower. The Hemato polyvalent antivenom also effectively protected mice from the lethal and local effects of H. hypnale venom in an in vivo rodent model of envenoming. Furthermore, the polyvalent antivenom could also effectively neutralize the venom of Daboia russelii (2.50mgvenom/mL antivenom), another common cause of snake bites in Sri Lanka and South India. These findings suggested that the Hemato polyvalent antivenom may be beneficial in the antivenom treatment of H. hypnale envenoming.

Acute Exposure to Ozone Exacerbates Acetaminophen-Induced Liver Injury in Mice

Ozone (O(3)), an oxidant air pollutant in photochemical smog, principally targets epithelial cells lining the respiratory tract. However, changes in gene expression have also been reported in livers of O(3)-exposed mice. The principal aim of the present study was to determine if acute exposure to environmentally relevant concentrations of O(3) could cause exacerbation of drug-induced liver injury in mice. Overdose with acetaminophen (APAP) is the most common cause of drug-induced liver injury in developed countries. In the present study, we examined the hepatic effects of acute O(3) exposure in mice pretreated with a hepatotoxic dose of APAP. C57BL/6 male mice were fasted overnight and then given APAP (300 mg/kg ip) or saline vehicle (0 mg/kg APAP). Two hours later, mice were exposed to 0, 0.25, or 0.5 ppm O(3) for 6 h and then sacrificed 9 or 32 h after APAP administration (1 or 24 h after O(3) exposure, respectively). Animals euthanized at 32 h were given 5-bromo-2-deoxyuridine 2 h before sacrifice to identify hepatocytes undergoing reparative DNA synthesis. Saline-treated mice exposed to either air or O(3) had no liver injury. All APAP-treated mice developed marked centrilobular hepatocellular necrosis that increased in severity with time after APAP exposure. O(3) exposure increased the severity of APAP-induced liver injury as indicated by an increase in necrotic hepatic tissue and plasma alanine aminotransferase activity. O(3) also caused an increase in neutrophil accumulation in livers of APAP-treated animals. APAP induced a 10-fold increase in the number of bromodeoxyuridine-labeled hepatocytes that was markedly attenuated by O(3) exposure. Gene expression analysis 9 h after APAP revealed differential expression of genes involved in inflammation, oxidative stress, and cellular regeneration in mice treated with APAP and O(3) compared to APAP or O(3) alone, providing some indications of the mechanisms behind the APAP and O(3) potentiation. These results suggest that acute exposure to near ambient concentrations of this oxidant air pollutant may exacerbate drug-induced liver injury by delaying hepatic repair.

Isolation, identification and necrotic activity of viridiol from Chalara fraxinea, the fungus responsible for dieback of ash

SummaryInvestigation of secondary metabolite production of Chalara fraxinea, the fungus responsible for dieback of ash, led to the isolation of the phytotoxin viridiol and the fungistatic compound viridin. Viridiol showed necrotic activity towards ash‐seedlings.

Biochemical Characterisation of an In Vitro Model of Hepatocellular Apoptotic Cell Death

This study was set up to critically evaluate a commonly-used in vitro model of hepatocellular apoptotic cell death, in which freshly isolated hepatocytes, cultured in a monolayer configuration, are exposed to a combination of Fas ligand and cycloheximide for six hours. A set of well-acknowledged cell death markers was addressed: a) cell morphology was studied by light microscopy; b) apoptotic and necrotic cell populations were quantified by in situ staining with Annexin-V, Hoechst 33342 and propidium iodide (PI); c) apoptotic and necrotic activities were monitored by probing caspase 3-like activity and measuring the extracellular leakage of lactate dehydrogenase (LDH), respectively; and d) the expression of apoptosis regulators was investigated by immunoblotting. The initiation of apoptosis was evidenced by the activation of caspase 8 and caspase 9, and increased Annexin-V reactivity. Progression through the apoptotic process was confirmed by the activation of caspase 3 and Bid, the enhanced expression of Bax, and the occurrence of nuclear fragmentation. Late transition to a necrotic appearance was demonstrated by an increased number of PI-positive cells and augmented extracellular release of LDH. Thus, the in vitro model allows the study of the entire course of Fas-mediated hepatocellular apoptotic cell death, which is not possible in vivo. This experimental system can serve a broad range of in vitro pharmaco-toxicological purposes, thereby directly assisting in the reduction of animal experimentation.

Effect of umbelliferone (7-hydroxycoumarin, 7-HOC) on the enzymatic, edematogenic and necrotic activities of secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus collilineatus venom

Flavonoids, coumarins and other polyphenolic compounds are powerful antioxidants both in hydrophilic and lipophylic environments with diverse pharmacological properties including anti-inflammatory activity. Despite being widely used as powerful therapeutic agents for blood coagulation disorders, more specifically to control some serine protease enzymes, the mechanism of anti-inflammatory activity of coumarins is unknown, unlike that of flavonoids. Although their controlling effect on serine proteases is well acknowledged, their action on secretory phospholipase A2 (sPLA2) remains obscure. The present study describes the interaction between umbelliferone (7-HOC) and the sPLA2 from Crotalus durissus collilineatus venom. In vitro inhibition of sPLA2 enzymatic activity by 7-HOC was estimated using 4N3OBA as substrate, resulting in an irreversible decrease in such activity proportional to 7-HOC concentration. The biophysical interaction between 7-HOC and sPLA2 was examined by fluorescent spectral analysis and circular dichroism studies. Results from both techniques clearly showed that 7-HOC strongly modified the secondary structure of this enzyme and CD spectra revealed that it strongly decreased sPLA2 alpha-helical conformation. In addition, two-dimensional electrophoresis indicated an evident difference between HPLC-purified native and 7-HOC-treated sPLA2s, which were used in pharmacological experiments to compare their biological activities. In vivo anti-inflammatory activity was assessed by the sPLA2-induced mouse paw edema model, in which 7-HOC presented an effect similar to those of dexamethasone and cyproheptadine against the pro-inflammatory effect induced by native sPLA2 on the mouse paw edema, mast cell degranulation and skin edema. On the other hand, 7-HOC exhibited a more potent inhibitory effect on sPLA2 than that of p-bromophenacyl bromide ( p-BPB). Our data suggest that 7-HOC interacts with sPLA2 and causes some structural modifications that lead to a sharp decrease or inhibition of the edematogenic and myotoxic activities of this enzyme, indicating its potential use to suppress inflammation induced by sPLA2 from the snake venom.

Design, synthesis and antitumor evaluation of novel thalidomide dithiocarbamate and dithioate analogs against Ehrlich ascites carcinoma-induced solid tumor in Swiss albino mice

A series of 16 novel thalidomide sulfur analogs containing one and two sulfur atoms 2 and 4– 18, respectively, were designed and synthesized. These compounds were screened for in vitro antitumor activity against Ehrlich ascites carcinoma (EAC) cell line and exhibited potent cytotoxic activity. On the bases of the obtained results for in vitro cytotoxic activity, thalidomide sulfur analogs containing two sulfur atoms 8, 9, 13 and 14 were selected and tested in vivo against EAC-induced solid tumor in female mice compared to thalidomide 1 as well as its analog 2 and exhibited a highly significant reduction in tumor volume (TV). Results illustrated the antioxidative activity of these compounds as the level of hepatic lipid peroxidation decreased and levels of antioxidant enzymes like superoxide dismutase (SOD) and catalase were elevated. The histopathological investigations revealed that thalidomide sulfur analogs 2, 8, 9, 13 and 14 have antimitotic, apoptotic and necrotic activities against solid tumor. These compounds lead to increase of Fas-L expression. The immunohistochemical studies showed a decrease in Ki67 and vascular endothelial growth factor (VEGF) staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate and angiogenic process associated with tumor growth. Compounds 9 and 13 were the most potent compounds in tumor necrosis without liver necrosis. At the same time, treatment with compound 9 resulted in liver degeneration.