Antihyperalgesic effect of γ-terpinene complexed in ß-cyclodextrin on neuropathic pain model induced by tumor cells.

Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in ß-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/ß-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x106 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and ß-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells.

Bioconjugate based on cisplatin and bacterial exopolysaccharide with reduced side effects: A novel proposal for cancer treatment.

BACKGROUND: In the search for alternatives that attenuate the toxicity associated to oncologic treatment with cisplatin (CDDP) and considering the potential health-beneficial properties of exopolysaccharides (EPS) produced by lactic acid bacteria, it was aimed on this study to evaluate the cytotoxic, toxicologic and antitumoral efficacy of a bioconjugate based on CDDP and EPS, on the experimental tumor of sarcoma 180. METHODS: After the synthesis of the cis-[Pt(NH3)2(Cl)2] complex and of the conjugate containing Lactobacillus fermentum exopolysaccharide was tested both in vitro and in vivo for evaluating the acute toxicity. RESULTS: The antitumoral study was performed using mice transplanted with sarcoma 180. The bioconjugate showed low to medium cytotoxicity for the cell lines tested, as well moderated acute toxicity. After determining the LD50, the following experimental groups were established for the antitumor assay: Control (NaCl 0,9%), CDDP (1 mg/kg), EPS and bioconjugate composition (200 mg/kg). The bioconjugate promoted a 38% regression in tumor mass when compared to the control, and a regression of 41% when compared to CDDP. Liver histopathological analysis revealed discrete alterations in animals treated with (CDDP + EPS) when compared to control. The bioconjugate also minimized changes in the renal parenchyma resulting from the tumor. CONCLUSION: Our results indicate that when CDDP is associated with EPS, this composition was more biocompatible, showing itself as a potent chemotherapeutic agent and lower tissue toxicity.

Toxicity and antitumor activity of the water-soluble lectin from Moringa oleifera Lam. Seeds (WSMoL) in sarcoma 180-bearing mice.

WSMoL, a water-soluble lectin from the seeds of Moringa oleifera, present several biological activities. This work aimed to evaluated the toxicity and antitumor activity of WSMoL. To analyze toxicity, it was determined hematological, biochemical and histological parameters; consumption of water and feed as well as the weight of the animals. Antitumor analysis included evaluation of tumor weight, histology and cytokine levels. Acute toxicity assay revealed 60% mortality of animals treated with lectin at 200 mg/kg i. p. At 100 mg/kg i. p., the animals showed a decreased food and water consumption as well weight gain in comparison with control. However, no animal died and there were no alterations in blood parameters or histological analysis. Antitumor activity evaluated at safe doses (2.5, 5 and 10 mg/kg) showed a significant reduction in tumor weight. Tumor photomicrographs evidenced that WSMoL treatment reduced dissemination of tumor cells. WSMoL (5 and 10 mg/kg) significantly enhance the immune function in the tumor environment as showed by increased the levels of pro-inflammatory (TNF-α, IFN-γ, IL-2, IL-6, and IL-17) and anti-inflammatory (IL-4 and IL-10) cytokines. In conclusion, WSMoL showed in vivo antitumor activity in mice bearing sarcoma 180 tumor, probably by increase the immune response against the tumor.

Ent-kaurenoic acid-enriched Mikania glomerata leaves-complexed ß-cyclodextrin: Pharmaceutical development and in vivo antitumor activity in a sarcoma 180 mouse model.

The extract obtained from Mikania glomerata leaves rich in ent-kaurenoic acid (ERKA) shows cytotoxic activity in vitro, but its hydrophobic nature and thermosensitivity are issues to be solved prior to in vivo antitumor studies. The purpose of this study was to investigate the antitumor activity of inclusion complexes formed between ERKA and ß-cyclodextrin (ERKA:ß-CD) in rodents. ERKA:ß-CD complexes obtained by malaxation (MX) and co-evaporation (CE) methods were firstly characterized regarding their physical properties, encapsulation efficiency, and cytotoxicity againts L929 cells. The antitumor activity study was then performed in mice with sarcoma 180 treated with saline, 5-fluouracil (5FU) and ERKA:ß-CD at 30, 100 and 300 µg/kg. The weight, volume, percentage of inhibition growth, gross and pathological features and positivity for TUNEL, ki67, NFκB and NRF2 in the tumors were assessed. Serum lactate-dehydrogenase activity (LDH), white blood cells count (WBC) and both gross and pathological features of the liver, kidneys and spleen were also evaluated. The formation of the inclusion complexes was confirmed by thermal analysis and FTIR, and they were non-toxic for L929 cells. The MX provided a better complexation efficiency. ERKA:ß-CD300 promoted significant tumor growth inhibition, and attenuated the tumor mitotic activity and necrosis content, comparable to 5-fluorouracil. ERKA:ß-CD300 also increased TUNEL-detected cell death, reduced Ki67 and NF-kB immunoexpression, and partially inhibited the serum LDH activity. No side effect was observed in ERKA:ß-CD300-treated animals. The ERKA:ß-CD inclusion complexes at 300 µg/kg displays antitumour activity in mice with low systemic toxicity, likely due to inhibition on the NF-kB signaling pathway and LDH activity.

α-Phellandrene exhibits antinociceptive and tumor-reducing effects in a mouse model of oncologic pain.

Medical reports indicate a prevalence of pain in 50% of patients with cancer. In this context, this article investigated the antinociceptive activity of α-PHE using in vivo Sarcoma-180-induced hypernociception in mice to detail its mechanism(s) of antinociception under different conditions of treatment and tumor progression. Firsty, in vitro cytotoxic action was assessed using melanoma B-16/F-10 and S-180 murine cells and colorimetric MTT assays. For in vivo studies, acute treatment with α-PHE (6.25, 12.5, 25 and 50 mg/kg orally by gavage) was performed on the 1st day after S-180 inoculation. Subacute treatments were performed for 8 days starting on the next day (early protocol) or on day 8 after S-180 inoculation (late protocol). For all procedures, mechanical nociceptive evaluations were carried out by von Frey's technique in the subaxillary region peritumoral tissue (direct nociception) and in right legs of S-180-bearing mice (indirect nociception). α-PHE showed in vitro cytotoxic action on B-16/F-10 and S-180 (CI50 values of 436.0 and 217.9 µg/mL), inhibition of in vivo tumor growth (ranging from 47.3 to 82.7%) and decreased direct (peritumoral tissue in subaxillary region) and indirect (right leg) mechanical nociception in Sarcoma 180-bearing mice with early and advanced tumors under acute or subacute conditions of treatment especially at doses of 25 and 50 mg/kg. It improved serum levels of GSH as well as diminished systemic lipid peroxidation, blood cytokines (interleukin-1ß, -4, -6, and tumor necrosis factor-α). Such outcomes highlight α-PHE as a promising lead compound that combines antinociceptive and antineoplasic properties. Its structural simplicity make it a cost-effective alternative, justifying further mechanistic investigations and the development of pharmaceutical formulations. Moreover, the protocols developed and standardized here make it possible to use Sarcoma-180 hypernociception model to evaluate the capacity of new antinociceptive molecules under conditions of cancer-related allodynia.

Antiproliferative and Genotoxic Action of an Underexploited Organoteluran Derivative on Sarcoma 180 Cells.

BACKGROUND: The search for novel metallic chemical compounds with toxicogenic effects has been of great importance for more efficient cancer treatment. OBJECTIVE: The study evaluated the cytotoxic, genotoxic and mutagenic activity of organoteluran RF07 in the S-180 cell line. METHODS: The bioassays used were cell viability with 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test, evaluation of apoptosis and necrosis using fluorescence and flow cytometry, cytokinesisblock micronucleus test and comet assay. The compound was tested at 1; 2.5 and 5µM. RESULTS: The results showed the cytotoxicity of RF07 at concentrations of 2.5, 5, 10 and 20µM when compared to the negative control. For genotoxicity tests, RF07 showed effects in all concentrations assessed by increased index and frequencies of damage and mutagenic alterations. The compound was also cytotoxic due to the significant decrease in the nuclear division index, with significant values of apoptosis and necrosis. The results of fluorescence and flow cytometry showed apoptosis as the main type of cell death caused by RF07 at 5µM, which is thought to avoid an aggressive immune response of the organism. CONCLUSION: In addition to cytotoxic and genotoxic effects, RF07 creates good perspectives for future antitumor formulations.

The Effects of the Alkaloid Tambjamine J on Mice Implanted with Sarcoma 180 Tumor Cells.

The tambjamines are a small group of bipyrrolic alkaloids that, collectively, display a significant range of biological activities including antitumor, antimicrobial and immunosuppressive properties. The key objective of the present study was to undertake preclinical assessments of tambjamine J (T-J) so as to determine its in vivo antitumor effects. To that end, sarcoma 180 cells were transplanted in mice and the impacts of the title compound then evaluated using a range of protocols including hematological, biochemical, histopathological, genotoxic and clastogenic assays. As a result it was established that this alkaloid has a significant therapeutic window and effectively reduces tumor growth (by 40 % and 79 % at doses of 10 and 20 mg/kg/day, respectively). In this regard it displays similar antitumor activity to the anticancer agent cyclophosphamide and alters animal weight in an analogous manner.

Antitumor activity of Moringa oleifera (drumstick tree) flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice.

The plant Moringa oleifera is used as food and medicine. M. oleifera flowers are source of protein, fiber, and antioxidants, and are used to treat inflammation and tumors. This work evaluated the antitumor activity of the M. oleifera flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice. Swiss female mice were inoculated with sarcoma 180 cells. Seven days later, the animals were treated intraperitoneally for 1 week with daily doses of PBS (control) or MoFTI (15 or 30 mg/kg). For toxicity assessment, water and food consumption, body and organ weights, histological alterations, and blood hematological and biochemical parameters were measured. Treatment with MoFTI caused pronounced reduction (90.1%-97.9%) in tumor weight. The tumors of treated animals had a reduced number of secondary vessels and lower gauge of the primary vessels compared to the control. No significant changes were observed in water and food consumption or in body and organ weights. Histopathological analysis did not indicate damage to the liver, kidneys, and spleen. In conclusion, MoFTI showed antitumor potential, with no clear evidence of toxicity.

Antitumor effects of citrinin in an animal model of Sarcoma 180 via cytogenetic mechanisms.

Citrinin (CIT) is a cytotoxic, hepatotoxic, nephrotoxic and cardiotoxic metabolite obtained from Penicillium citrinum, that has been increasingly searched as an anticancer drug candidate. In this study, we assessed the antitumor effects of citrinin, using cytogenetic biomarkers for genotoxicity in Sarcoma 180 (S-180) ascitic fluid cells of mice. Citrinin, extracted from P. citrinum acetonitrile extract, was characterized by LC-MS. Cytotoxic assessment was done through using comet (alkaline version) and micronucleus assays. In S-180 cells, CI50 of CIT was 3.77 µg/mL, while at 12.5 and 100 µg/mL, CIT was as cytotoxic as doxorubicin (2 µg/mL). At 0.5, 1.0 and 2.0 µg/mL, it induced genotoxicity and mutagenicity in S-180 cells, especially at 2 µg/mL, triggering oxidative damage similar to hydrogen peroxide (10 mM). The antitumor effects were evidenced by a marked increase in S-180 cells apoptosis and necrosis due to clastogenic and/or aneugenic cytogenetic effects (micronucleus formation), as well as by induction of nucleoplasm bridges and nuclear buds, culminating in S-180 apoptosis and necrosis. CIT has potential as drug candidate for antitumor purposesbyinvolving cytogenetic mechanisms.

Antinociceptive activity of Schinus terebinthifolia leaf lectin (SteLL) in sarcoma 180-bearing mice.

ETHNOPHARMACOLOGY RELEVANCE: Schinus terebinthifolia Raddi leaves have been used in folk medicine due to several properties, including antitumor and analgesic effects. The variable efficacy and adverse effects of analgesic drugs have motivated the search for novel antinociceptive agents. It has been reported that the S. terebinthifolia leaf lectin (SteLL) has antitumor activity against sarcoma 180 in mice. AIM OF THE STUDY: This work aimed to evaluate whether SteLL would reduce cancer pain using an orthotopic tumor model. MATERIALS AND METHODS: A sarcoma 180 cell suspension was inoculated into the right hind paws of mice, and the treatments (150 mM NaCl, negative control; 10 mg/kg morphine, positive control; or SteLL at 1 and 2 mg/kg) were administered intraperitoneally 24 h after cell inoculation up to 14 days. Spontaneous nociception, mechanical hyperalgesia, and hot-plate tests were performed. Further, the volume and weight of the tumor-bearing paws were measured. RESULTS: SteLL (2 mg/kg) improved limb use during ambulation. The lectin (1 and 2 mg/kg) also inhibited mechanical hyperalgesia and increased the latency time during the hot-plate test. Naloxone was found to reverse this effect, indicating the involvement of opioid receptors. The tumor-bearing paws of mice treated with SteLL exhibited lower volume and weight. CONCLUSION: SteLL reduced hyperalgesia due to sarcoma 180 in the paws of mice, and this effect can be related to its antitumor action.

Evaluation of antitumor activity and toxicity of Schinus terebinthifolia leaf extract and lectin (SteLL) in sarcoma 180-bearing mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Schinus terebinthifolia Raddi is a plant broadly used in folk medicine and the use of its leaf extract as an antitumor agent has been reported. AIM OF THE STUDY: To evaluate the antitumor potential and the toxicity of saline extract (SE) and lectin (SteLL) from S. terebinthifolia leaves in sarcoma 180-bearing mice. MATERIALS AND METHODS: Cytotoxicity to sarcoma 180 cells was tested in vitro, and antitumor assay was performed using Swiss female mice. The treatments (0.15 M NaCl, negative control; methotrexate 1.5 mg/kg, positive control; SE 100 mg/kg; SteLL 1 and 5 mg/kg) by intraperitoneal injections started on the 8th day after tumor inoculation and lasted 7 days. It was analyzed: tumor weight; number and gauge of tumor vessels; hematological and biochemical parameters; histopathological changes; and occurrence of micronuclei in bone marrow cells. RESULTS: SE and SteLL showed IC50 values (concentrations that reduced cell viability to 50%) of 301.65 and 8.30 µg/mL, respectively. The lectin was able to induce apoptosis. Treatments with the extract and lectin caused a 57.6-73.6% reduction in tumor weight, which was not significantly different from the reduction in the methotrexate group. Tumors of animals treated with SteLL at 5 mg/kg showed reduced number of secondary vessels while the gauge was lower in all treated groups. In the groups treated with SteLL, tumors showed reduced and slightly vascularized parenchyma, with necrosis in the center and at the periphery. No alterations in the blood levels of urea, creatine, and glucose were detected while serum AST level was moderately increased in the SE group. Histopathological analysis revealed vacuolization and steatosis in the liver of animals treated with the extract and lectin. In addition, the treatments with SE and SteLL resulted in the reduction of filtration space and alterations in tubular architecture in kidneys. In respect to hematological parameters, it was only detected increase in the number of monocytes in SE group. The extract and lectin did not induce the formation of micronuclei in the bone marrow cells. CONCLUSIONS: SE and SteLL had antitumor effect against sarcoma 180 without inducing hematological changes and genotoxic effects in mice; however, some degree of hepatic and renal toxicity was observed, suggesting the evaluation of drug delivery strategies in the future.

Himatanthus drasticus (Apocynaceae) latex reduces oxidative stress and modulates CD4+, CD8+, FoxP3+ and HSP-60+ expressions in Sarcoma 180-bearing mice.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil, latex of Himatanthus drasticus is used to treat inflammation, wound healing and cancer. The present study evaluated the antitumoral potential of H. drasticus latex (HdCL) in Sarcoma 180-bearing mice (S180). MATERIALS AND METHODS: HdCL was obtained in Crato-CE, Brazil. Qualitative phytochemicals assays, nuclear magnetic resonance (NMR) and microbiological analyzes were performed. Swiss mice were divided into six groups, according to tumor forms: 1) ascitic model, GI (Control; 0.9% saline), GII (S180asc) and GIII (S180asc/HdCL/14 days); 2) solid model, GIV (Control; 0.9% saline), GV (S180sol) and GVI (S180sol/HdCL/10 days). HdCL and 0.9% saline were administered at 0.2 mL, SID, by gavage, for 10 or 14 days. For ascitic model, 0.5 mL of S180 suspension (4×106 cells/mL) was inoculated intraperitoneally and for solid model, cells were inoculated subcutaneously (25 µL) on the right hind paw of mice. Blood samples were collected for hematological and oxidative stress evaluation. Thickness, volume and weight of paws were measured in solid model. After euthanasia, spleen, liver and kidney were collected in order to assess the relative organ weight. Tissue fragments of paws and popliteal lymph nodes (PLN) were analyzed by H&E and CD4+, CD8+, HSP-60+ and Foxp3+ immunohistochemistry. RESULTS: HdCL presented milky aspect and pinkish supernatant. Phenols, flavonols, flavanones, free steroids and cinnamoyl derivatives of lupeol, α-amyrin and ß-amyrin were detected at the phytochemistry analysis. HdCL did not alter the relative weight of organs, hematological parameters and volume of ascitic fluid recovered. In solid model, HdCL reduced (P < 0.05) paw volume, but did not altered thickness, paw weight and histological parameters. S180sol induced necrosis, metastasis and destruction of bone, cartilage and muscles. Bleeding, vessel congestion and oncocytes were observed in PLN. In paw, HdCL did not alter FoxP3+ and HSP-60+ expressions but reduced the CD4+ and CD8+ expressions, while at PLN, HdCL reduced the expressions of all markers. HdCL decreased (P < 0.05) serum levels of malondialdehyde in ascitic model. CONCLUSIONS: Treatment with HdCL reduced oxidative damage and modulated the expressions of CD4+, CD8+, FoxP3+and HSP-60+ in S180 solid tumor model, which can be associated to the presence of triterpenes, such as α-amyrin, ß-amyrin and lupeol cinnamate. Present data emphasizes the importance of immune system in cancer and highlights the evaluation of the pharmacological properties of plants used by population as phytoterapics.

A polysaccharide fraction extracted from Pleurotus ostreatus mycelial biomass inhibit Sarcoma 180 tumor.

Fungi of Pleurotus genus have attracted a great interest due to their medicinal properties such as anti-inflammatory, antimicrobial and antitumor. These properties are attributed mainly to polysaccharides synthesized by Pleurotus. This work aimed to study the mycelial growth of P. ostreatus in submerged culture, evaluating the influence of the initial concentration of substrate (20 and 40 g/L of glucose) and the pH (4 and 6) on kinetic parameters of production of biomass. The effectiveness of different doses (10, 30 and 50 mg/kg) of a mycelium polysaccharide fraction extracted from P. ostreatus in reducing Sarcoma 180 development in mice was also verified. In the range of this study, maximum concentration of mycelial biomass (about 12.8 g/L) was obtained using 40.0 g/L of glucose, at pH 4.0. The total biomass productivity (Px) was not significantly affected by substrate concentration and pH, reaching values of 0.034 g/L.h. Sarcoma 180 tumor weight was reduced in 74.1, 75.5 and 53.7% when 10, 30 and 50 mg/kg were administered, respectively. These results show the high antitumor potential of intracellular polysaccharide fraction of mycelial biomass of P. ostreatus, particularly at lower doses of 10 and 30 mg/kg.

A polysaccharide fraction extracted from Pleurotus ostreatus mycelial biomass inhibit Sarcoma 180 tumor

ABSTRACT Fungi of Pleurotus genus have attracted a great interest due to their medicinal properties such as anti-inflammatory, antimicrobial and antitumor. These properties are attributed mainly to polysaccharides synthesized by Pleurotus. This work aimed to study the mycelial growth of P. ostreatus in submerged culture, evaluating the influence of the initial concentration of substrate (20 and 40 g/L of glucose) and the pH (4 and 6) on kinetic parameters of production of biomass. The effectiveness of different doses (10, 30 and 50 mg/kg) of a mycelium polysaccharide fraction extracted from P. ostreatus in reducing Sarcoma 180 development in mice was also verified. In the range of this study, maximum concentration of mycelial biomass (about 12.8 g/L) was obtained using 40.0 g/L of glucose, at pH 4.0. The total biomass productivity (Px) was not significantly affected by substrate concentration and pH, reaching values of 0.034 g/L.h. Sarcoma 180 tumor weight was reduced in 74.1, 75.5 and 53.7% when 10, 30 and 50 mg/kg were administered, respectively. These results show the high antitumor potential of intracellular polysaccharide fraction of mycelial biomass of P. ostreatus, particularly at lower doses of 10 and 30 mg/kg.

Agaricus subrufescens: substratum nitrogen concentration and mycelial extraction method on antitumor activity.

Antitumor activity of Agaricus subrufescens has been shown on vegetative mycelium and basidiocarp. However, few studies have assessed the effect of A. subrufescens cultivation conditions and extraction methods on antitumor activity. This study evaluated the effect of nitrogen concentration on the cultivation medium of A. subrufescens and the extraction method of mycelial antineoplastic actives against sarcoma 180 cells implanted in mice. Two nitrogen sources (isolated soybean protein and NaNO3) and 10 nitrogen concentrations (0.25 to 8.0 g/L) were used. Dried mycelium extract was obtained by hot water infusion (1:10 mass:volume; 90 °C) or by aqueous mixture (1:10 mass:volume, ambient temperature) in ultrapure water. The doses were administered daily by gavage to mice implanted with sarcoma 180 cells. Isolated soy protein is more efficient to mycelial biomass production than NaNO3. The mycelial biomass production increases when the cultivation medium is added with high nitrogen concentrations as well as the splenic index and the antitumor activity of the moistened mycelial powder. Hot water extract is more effective than the moistened mycelial powder to reduce tumor. The antitumor activity of hot water mycelial extract is similar to the one of basidiocarps, presenting lower metabolic demand on the spleen, keeping blood parameters normal and promoting animal wellness.

Effect of the extract from leaves of Liquidambar formosana Hance on S180 cells.

We examined the effects of the extract from leaves of Liquidambar formosana Hance on S180 cells and screened for antitumor active sites in the plant. Solvent extraction was conducted to prepare extracts from the leaves of L. formosana Hance and conduct preliminary separation, an MTT assay to determine the effect of leaf extract on the proliferation of S180 cells, and inverted microscopy to observe the effect of chloroform extract on the morphology of S180 cells. Double-staining (Annexin V/propidium iodide) with flow cytometry was conducted to determine the effect of the chloroform extract on S180 cell apoptosis. At some concentrations, the different extracts from the leaves of L. formosana Hance dose-dependently inhibited the proliferation of S180 cells. Among all extracts, the chloroform extract showed the strongest inhibitory effect on S180 cell proliferation. The IC50 values for the chloroform extract, ethyl acetate extract, n-butanol extract, and water layer were 0.238, 0.471, 0.844, and 0.411 mg/mL, respectively. We observed cell shrinkage, volume reduction, and varying sizes by inverted microscopy. Additionally, with increasing drug concentration, the number of cells decreased and debris increased. The cells showed typical apoptotic morphological changes. The chloroform extract induced the apoptosis of S180 cells in a dose-dependent manner. Different extracts from the leaves of L. formosana Hance inhibited the proliferation of S180 cells, and the chloroform extract was the main antitumor component. This extract from the leaves of L. formosana Hance inhibited the proliferation of S180 cells in part by inducing apoptosis.

Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin.

Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.

Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice.

Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.

Indigofera suffruticosa Mill (Fabaceae): hepatic responses in mice bearing sarcoma 180 / Indigofera suffruticosa Mill (Fabaceae): respuestas hepáticas en ratones portadores de sarcoma 180

Indigofera suffruticosa is a plant generally used to treat infectious and inflammatory processes. This work aims to evaluate the histopathological changes in the liver tissue of mice with Sarcoma 180 after subchronic treatment with aqueous extract obtained by infusion and maceration of Indigofera suffruticosa leaves. Male mice were divided into four groups of six animals: G1, G2 and G3 patients with Sarcoma 180 and Sarcoma 180 G4 without sarcoma. G1 and G2 were treated with infusion mashing respectively (50 mg/kg ip); G3 and G4 controls received saline (15 ml/kg ip). The histopathological and morphometric analysis of liver tissue after subchronic treatment with aqueous extracts by infusion and maceration of the groups G1, G2 and G4 were similar and showed no degraded areas or leukocyte infiltration compared to G3, which shows a marked destruction of liver architecture. The results showed that after subchronic treatment with the aqueous extract of leaves Indigofera Suffruticosa obtained by infusion and maceration, the hepatic architecture was preserved, suggesting its use as an alternative hepatoprotective agent.

Indigofera suffruticosa es una planta utilizada para tratar procesos infecciosos e inflamatorios. Este trabajo tiene como objetivo evaluar los cambios histopatológicos en el tejido del hígado de ratones con sarcoma 180 después del tratamiento subcrónica con el extracto acuoso obtenido por infusión y maceración de las hojas de Indigofera suffruticosa. Los ratones machos fueron divididos en cuatro grupos de seis animales: pacientes G1 , G2 y G3 con Sarcoma 180 y G4 sin Sarcoma. G1 y G2 fueron tratados con infusión de maceración respectivamente (50mg/kg.ip); Controles G3 y G4 recibieron solución salina (15 ml/kg.ip). El análisis histopatológico y morfométrico de tejido hepático después de un tratamiento subcrónico con extractos acuosos por infusión y la maceración de los grupos G1, G2 y G4 fueron similares y no mostraron áreas degradadas o la infiltración de leucocitos en comparación a G3, que muestra una marcada destrucción de la arquitectura del hígado. Los resultados mostraron que después de un tratamiento subcrónico con el extracto acuoso de hojas de Indigofera suffruticosa obtenidos por infusión y la maceración, se conservó la arquitectura hepática, lo que sugiere su uso como una alternativa de agente hepatoprotector.

Antitumor activity of Pleurotus ostreatus polysaccharide fractions on Ehrlich tumor and Sarcoma 180.

The medicinal properties of fungi of the genus Pleurotus have attracted great interest due to their therapeutic properties. Polysaccharides synthesized by Pleurotus, including the ß-glucans are considered the main responsible for its therapeutic properties. This study aimed to evaluate the efficacy of polysaccharidic fractions extracted from mycelial biomass of Pleurotus ostreatus DSM 1833 in inhibiting the development of Ehrlich Tumor (ET) and Sarcoma 180 (S-180). FC, FI and FII fractions provided 60.6, 76.5 and 73.6% of ET inhibition, respectively (mean value of about 70%) while FS, FIII-1 and FIII-2 showed no inhibition against ET. FII and FIII-2 resulted in 85.6 and 93.6% (mean value of about 90%) while FIII-1, FC and FS resulted in 54.1 and 0%, respectively, of S-180 inhibition. The yields of the fractions FS, FI, FII, FIII-1 and FIII-2 obtained from P. ostreatus mycelial biomass were 11.6, 1.3, 0.4, 0.65 and 0.35%, respectively. FII fraction (30mg/kg) apparently had no toxic effect on healthy animals, since no difference between the body weights of animals in substance control (SC) and negative control (NC) groups was observed.