Iberverin exhibits antineoplastic activities against human hepatocellular carcinoma via DNA damage-mediated cell cycle arrest and mitochondrial-related apoptosis.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high incidence and mortality rates in the world. Isothiocyanates (ITCs), bioactive substances present primarily in the plant order Brassicales, have been proved to be promising candidates for novel anti-HCC drugs with chemopreventive and anticancer activities. Iberverin, a predominant ITC isolated from the seeds of oxheart cabbage, has been discovered with anticancer property in lung cancer cells. However, the roles of iberverin in HCC remain elusive. In the present study, the effect and potential mechanisms of iberverin against human HCC were dissected. We demonstrated that low concentrations of iberverin inhibited cell proliferation, suppressed migration and induced mitochondrial-related apoptosis in vitro, and hampered tumorigenicity in vivo, with no obvious toxicity. Furthermore, we found that iberverin treatment induced DNA damage and G2/M phase arrest. Iberverin treatment also caused increased intracellular reactive oxygen species formation and glutathione depletion. Taken together, these results suggest that iberverin promotes mitochondrial-mediated apoptosis and induces DNA damage and G2/M cell cycle arrest in HCC by enhancing oxidative stress. Our findings provide better understanding of the anti-HCC mechanisms of ITCs and the potential for the natural product iberverin as a promising new anti-HCC biotherapeutic.

Research progress on the anticancer activity of plant polysaccharides.

Tumor is a serious threat to human health, with extremely high morbidity and mortality rates. However, tumor treatment is challenging, and the development of antitumor drugs has always been a significant research focus. Plant polysaccharides are known to possess various biological activities. They have many pharmacological properties such as immunomodulation, antitumor, antiviral, antioxidative, antithrombotic, and antiradiation effects, reduction of blood pressure and blood sugar levels, and protection from liver injury. Among these effects, the antitumor effect of plant polysaccharides has been widely studied. Plant polysaccharides can inhibit tumor proliferation and growth by inhibiting tumor cell invasion and metastasis, inducing cell apoptosis, affecting the cell cycle, and regulating the tumor microenvironment. They also have the characteristics of safety, high efficiency, and low toxicity, which can alleviate, to a certain extent, the adverse reactions caused by traditional tumor treatment methods such as surgery, radiotherapy, and chemotherapy. Therefore, this paper systematically summarizes the direct antitumor effects of plant polysaccharides, their regulatory effects on the tumor microenvironment, and intervening many common high-incidence tumors in other ways. It also provides data support for the administration of plant polysaccharides in modern tumor drug therapy, enabling the identification of new targets and development of new drugs for tumor therapy.

Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin.

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10-20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes' ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65-8.99 µM and 9.24-13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.

Expression of recombinant human interleukin-29-Fc fusion protein in HEK293F cells and analysis of its anti-tumor activity in vitro / 中国生物制品学杂志

@#Objective To express recombinant human interleukin-29-Fc(rhIL-29-Fc) fusion protein in human embryonic kidney 293-F(HEK293F) cells and analyze its anti-tumor activity in vitro.Methods The recombinant expression plasmid UCOE-IL-29-Fc was constructed and transiently transfected into HEK-293F cells.After expression and purification,rhIL-29-Fc fusion protein was obtained and identified by SDS-PAGE and Western blot;Female Japanese white rabbits were immunized with rhIL-29 and rhIL-29-Fc protein subcutaneously in the left ear respectively,2 rabbits in each group,0.5 mg per rabbit.Blood samples were collected from the vein of right ear,and the serum was separated.The half-life was measured by ELISA and the anti-proliferation effect of rhIL-29-Fc protein on human colon cancer HT-29,human colon cancer HCT-116,human Burkkit lymphoma Daudi,human non-small cell lung cancer NCI-H1975,human small cell lung cancer NCI-H209,human esophageal cancer EC109 and human pancreatic cancer PANC-1 cells in vitro was detected by CCK-8 assay,and the inhibitory concentration 50(IC_(50)) was calculated.Results The recombinant expression plasmid UCOE-IL-29-Fc was constructed correctly as identified by double digestion and sequencing.After transient transfection into HEK-293 cells for 6 d,the culture supernatant was harvested.The relative molecular mass of the purified rhIL-29-Fc fusion protein was consistent with the expectation.The protein showed a specific binding reaction with mouse anti-human IL-29 monoclonal antibody with a concentration of 1.5 mg/ml and a purity of 93%.RhIL-29-Fc protein had a half-life of 25 h and showed different inhibitory effects on the proliferation of 7 kinds of tumor cells,and the IC_(50) on different cells was also different.Conclusion The rhIL-29-Fc fusion protein was successfully expressed in HEK-293F cells,and the half-life of the fusion protein was 20 h longer than that of rhIL-29.According to the different anti-tumor proliferation activity in vitro and IC_(50) results on 7 kinds of tumor cells,it was found that the anti-tumor activity of rhIL-29-Fc fusion protein was higher than that of rhIL-29.This study laid a foundation of the development of IL-29 protein in the treatment of tumors.

Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2V617F driven cells.

Myeloproliferative neoplasms (MPN) belong to a group of clonal diseases of hematopoietic stem cells characterized by aberrant proliferation of mature myeloid lineages. The constitutive activation of the JAK2/STAT signaling pathway is now well established to play a central role in MPN pathogenesis; however, accumulating evidence now indicates that the IGF1R-mediated signaling pathway contributes to the maintenance of the malignant phenotype. Studies using inhibitors of IGF1-mediated signaling have reported cytotoxic effects in cellular and murine models of MPN, but no consensus has been reached regarding the potency and efficacy of inhibitors of the IGF1R-related pathway in this context. In the present study, we compared the potency and efficacy of three inhibitors of IGF1R-related pathways in a JAK2V617F-driven cellular model. These inhibitors (NT157, OSI-906, and NVP-AEW54) present antineoplastic activity with similar efficacy in Ba/F3 JAK2V617F cells, with NT157 showing the greatest potency. Both the induction of apoptosis and reduction in cell proliferation were associated with the observed reduction in cell viability. Downregulation of JAK2/STAT signaling was an advantageous off-target effect of all three inhibitors. These preclinical studies reinforce the potential of the IGF1R-related pathway as a therapeutic target in MPN.

Cipacinerasins A-K, structurally diverse limonoids from Cipadessa baccifera.

Eleven undescribed limonoids, cipacinerasins A-K, involving of four diverse carbon skeletal types, along with fifteen known analogues, were isolated from the branches and leaves of Cipadessa baccifera. Within them, cipacinerasins A and B feature a rearranged tetrahydropyranyl ring B formed between C-8 and C-30, are unusual miscellaneous-type limonoids. Cipacinerasins E and F are rare trijugin-type limonoids, of which the D-ring δ-lactone is cleaved. Their structures were elucidated on the basis of extensive spectroscopic data (HRESIMS, NMR, UV and IR), electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. All compounds were evaluated in vitro cytotoxicity against five human tumor cell lines (K562, HeLa, PC3, LN-Cap and Hell), and cipacinerasin E showed moderate antitumor activity with IC50 values ranging from 8.0 to 24.8 µM.

NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells.

Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer.

Tris(2-Pyridylmethylamine)V(O)2 Complexes as Counter Ions of Diprotonated Decavanadate Anion: Potential Antineoplastic Activity.

The synthesis and theoretical-experimental characterization of a novel diprotanated decavanadate is presented here due to our search for novel anticancer metallodrugs. Tris(2-pyridylmethyl)amine (TPMA), which is also known to have anticancer activity in osteosarcoma cell lines, was introduced as a possible cationic species that could act as a counterpart for the decavanadate anion. However, the isolated compound contains the previously reported vanadium (V) dioxido-tpma moieties, and the decavanadate anion appears to be diprotonated. The structural characterization of the compound was performed by infrared spectroscopy and single-crystal X-ray diffraction. In addition, DFT calculations were used to analyze the reactive sites involved in the donor-acceptor interactions from the molecular electrostatic potential maps. The level of theory mPW1PW91/6-31G(d)-LANL2DZ and ECP = LANL2DZ for the V atom was used. These insights about the compounds' main interactions were supported by analyzing the noncovalent interactions utilizing the AIM and Hirshfeld surfaces approach. Molecular docking studies with small RNA fragments were used to assess the hypothesis that decavanadate's anticancer activity could be attributed to its interaction with lncRNA molecules. Thus, a combination of three potentially beneficial components could be evaluated in various cancer cell lines.

A flavone from the ethyl acetate extract of Leea rubra leaves with DNA damage protection and antineoplastic activity.

Among the major constituents of Leea rubra (Family Vitaceae) leaves, phenolic and flavonoind compounds are most important for therapeutic purposes and the plant parts have been used in traditional medicine to treat several diseases for long. Thus, in order to scientifically confirm the traditional uses of the L. rubra leaves, the present study was designed to investigate the efficacy of the isolated flavones against AAPH induced oxidative damage to pUC19 DNA by gel electrophoresis and antineoplastic activity was evaluated on Ehrlich ascites carcinoma (EAC) bearing Swiss albino mice by evaluating percentage inhibition of cell growth, morphological changes of EAC cells and hematological parameters of the mice. The isolation was carried out by column chromatography and structure was revealed by 1H-NMR and 13C NMR. The result shows that, the isolated compound was identified as myricetin 4'-methoxy-3-O-α-l-rhamnopyranoside based on previously reported data. The isolated flavone effectively inhibited AAPH-induced oxidative damage to DNA; because it could inhibit the formation of circular and linear forms of the DNA. In anti-proliferative assay, 76% growth inhibition of EAC cells was observed as compare to the control mice (p<0.05) at a dose 100 mg/kg body weight. Thus the isolated flavone showed great importance as a possible therapeutic agent in preventing oxidative damage to DNA and the chronic diseases caused by such DNA damage, and can also become important in cancer chemotherapy.

Dibenzoylmethane derivative inhibits melanoma cancer in vitro and in vivo through induction of intrinsic and extrinsic apoptotic pathways.

Malignant melanoma has a low incidence, but is the most lethal type of skin cancer. Studies have shown that dibenzoylmethanes (DBMs) have interesting biological activities, including antineoplastic properties. These findings led us to investigate whether news DBM derivatives exert antitumor effects against skin cancers. In a previous study, we found that 1,3-diphenyl-2-benzyl-1,3-propanedione (DPBP) has high in vitro antineoplastic activity against murine B16F10 melanoma cells, with an IC50 of 6.25 µg/mL. In the current study, we used transdermal and topical formulations of DPBP to evaluate its activity and molecular mechanism of action in a murine model of melanoma. The compound induces tumor cell death with high selectivity (selectivity index of 41.94) by triggering apoptosis through intrinsic and extrinsic pathways. DPBP treatment reduced tumor volume as well as serum VEGF-A and uric acid levels. Hepatomegaly and nephrotoxicity were not observed at the tested doses. Histopathological analysis of sentinel lymph nodes revealed no evidence of metastases. According to the observed data, the DPBP compound was effective for the topical treatment of melanoma cancer, suggesting that it acts as a chemotherapeutic or chemopreventive agent.

Antitumor activity of Koningic acid in thyroid cancer by inhibiting cellular glycolysis.

PURPOSE: Koningic acid (KA), a sesquiterpene lactone, has been identified as an antimicrobial agent. Recent studies have revealed KA's antitumor activities in colorectal cancer, leukemia, and lung cancer. However, its antitumor effect in thyroid cancer remains largely unknown. METHODS: The effects of KA on proliferation, colony formation, apoptosis in thyroid cancer cells were assessed by MTT assay and flow cytometry. After KA treatment, the glycolysis ability of thyroid cancer cells was detected by ECAR, and the glycolytic products and relative ATP levels were measured by ELISA. The underlying mechanisms of antineoplastic activity of KA in thyroid cancer were detected by Western blot. Finally, the antineoplastic activity in vivo was observed in Xenograft mouse models. RESULTS: KA inhibited the proliferation, colony formation, and increased cell apoptosis in thyroid cancer cell lines in a dose and time-dependent manner. We verified that the glycolysis ability, ATP production, and lactic acid level in thyroid cancer cells had experienced an extensive decrease after KA treatment. In addition, lactic acid, the metabolite of glycolysis, could weaken the effect of KA on its colony formation ability in C643 thyroid cancer cell line. Our data also showed that KA kills thyroid cancer cells by inhibiting the MAPK/ERK pathway and decreasing Bcl-2 level. By contrast with the control group, the growth of xenograft tumor was dramatically inhibited by KA without obvious drug side effects. CONCLUSION: Our data demonstrate that KA kills thyroid cancer cell lines by inhibiting their glycolysis ability, the MAPK/ERK pathway and the Bcl-2 level and suggest that KA has potential clinical value in thyroid cancer therapy.

4-Thiofuranoid Glycal: Versatile Glycosyl Donor for the Selective Synthesis of ß-anomer of 4'-thionucleoside and its Biological Activities.

The first highly diastereoselective synthesis of ß-anomers of 4'-thionucleosides has been carried out by means of electrophilic glycosidation utilizing 3,5-O-(di-tertbutylsilylene) (DTBS)-4-thiofuranoid glycal as a glycosyl donor. The resulting glycosides were transformed into ribo-, 2'-deoxy-, and arabinofuranosyl nucleosides through a chemical transformation of the 2'-substituent. The additive Pummerer reaction of the glycal Soxide gave 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose. The utility of the DTBSprotected 4-thioribofuranose has been demonstrated by the preparation of 4'-thio analogues of pyrimidine- and purine-4'-thioribonucleosides based on the Vorbrüggen glycosidation. Synthesis of 4'-thio-counterpart of C-nucleoside antibiotic tiazofurin has also been carried out. α-Face selective hydroboration of 1-C-aryl- or 1-C-heteroaryl-glycals obtained by cross-coupling of 1-tributylstannylglycal has furnished the respective ß- anomer of 4'-thio-C-ribonucleosides, including 4'-thio analogue of nucleoside antibiotic pseudouridine and 9-deazaadenosine. On the basis of lithiation chemistry, 1-C- and 2-Ccarbon- carbon-substituted 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3- diyl) (TIPDS)- 4- thiofuranoid glycal were synthesized. These glycals enabled us to prepare 1'-C- and 2'-ß- C-carbon-substituted 2'-deoxy-4'-thionucleosides, including thio-counterpart of antitumor nucleoside antibiotic angustmycin C. Furthermore, 1'-C-methyl-4'-thiothymidine emerged as a potent inhibitor of angiogenesis. In addition, 1'-C-methyl-4'-thiothymidine exhibited more potent inhibitory activity against thymidine kinase-deficient mutant of herpes virus than that of ganciclovir. Among the 4'-substituted 4'-thiothymidines, the 4'- C-cyano- and 4'-C-ethynyl derivatives inhibited replication of HIV variant resistant to 3TC (HIVM184V) as potently as HIV-1IIIB. In terms of the value of selectivity index (SI), 4'-C-cyano-4'-thiothymidine showed a 3-fold selective index (SI) than that of the corresponding thymidine derivative. Furthermore, 4'-C-ethynyl-2'-deoxy-4'-thioguanosine has a 20-fold better value (>18,200) than that of 2'-deoxyguanosine counterpart (933). Furthermore, 4'-azido-4'-thiothymidine emerged as a selective and potent anti-EBV agent. In terms of antineoplastic activity, 4'-azido- and 4'-C-fluoromethyl-2'-deoxy-4'-thiocytidine inhibited proliferation of human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines, although the parent compound 2'-deoxy-4'-thiocytidine did not exhibit any cytotoxicity up to 100 µM. These facts concerning the biological activities suggested that replacement of the furanose oxygen with a sulfur atom is a promising approach for the development of less toxic antiviral and antineoplastic nucleoside antimetabolites. 4'- Thionucleoside also acts as a monomer for oligonucleotides (ONs) therapeutics, exhibiting superior biological properties. Therefore, this review provides a wide range of potential monomers for antisense ON and siRNA.

Redox-Modulating Capacity and Antineoplastic Activity of Wastewater Obtained from the Distillation of the Essential Oils of Four Bulgarian Oil-Bearing Roses.

The wastewater from the distillation of rose oils is discharged directly into the soil because it has a limited potential for future applications. The aim of the present study was to determine in vitro the chromatographic profile, redox-modulating capacity, and antineoplastic activity of wastewater obtained by distillation of essential oils from the Bulgarian Rosa alba L., Rosa damascena Mill., Rosa gallica L., and Rosa centifolia L. We applied UHPLC-HRMS for chromatographic analysis of rose wastewaters, studied their metal-chelating and Fe(III)-reducing ability, and performed MTT assay for the evaluation of cytotoxic potential against three tumorigenic (HEPG2-hepatocellular adenocarcinoma, A-375-malignant melanoma, A-431-non-melanoma epidermoid squamous skin carcinoma) and one non-tumorigenic human cell lines (HaCaT-immortalized keratinocytes). The median inhibitory concentrations (IC50) were calculated with nonlinear modeling using the MAPLE® platform. The potential of the wastewaters to induce apoptosis was also examined. Mono-, di-, and acylated glycosides of quercetin and kaempferol, ellagic acid and its derivatives as main chemical components, and gallic acid and its derivatives-such as catechin and epicatechin-were identified. The redox-modulating capacity of the samples (TPTZ test) showed that all four wastewaters exhibited the properties of excellent heavy metal cleaners, but did not exert very strong cytotoxic effects. The lowest IC50 rate was provided in wastewater from R. centifolia (34-35 µg/mL of gallic acid equivalents after a 72 h period for all cell lines). At 24 and 48 hours, the most resistant cell line was HEPG2, followed by HaCaT. After 72 h of exposure, the IC50 values were similar for tumor and normal cells. Still, R. damascena had a selectivity index over 2.0 regarding A-431 non-melanoma skin cancer cells, showing a good toxicological safety profile in addition to moderate activity-IC50 of 35 µg/mL polyphenols. The obtained results related to wastewaters acquired after the distillation of essential oils from the Bulgarian R. alba, R. damascena, R. gallica, and R. centifolia direct our attention to further studies for in-depth elucidation of their application as detoxifying agents under oxidative damage conditions in other experimental datasets.

Antineoplastic Activity of Rhus trilobata Nutt. (Anacardiaceae) against Ovarian Cancer and Identification of Active Metabolites in This Pathology.

Rhus trilobata (RHTR) is a medicinal plant with cytotoxic activity in different cancer cell lines. However, the active compounds in this plant against ovarian cancer are unknown. In this study, we aimed to evaluate the antineoplastic activity of RHTR and identify its active metabolites against ovarian cancer. The aqueous extract (AE) and an active fraction (AF02) purified on C18-cartridges/ethyl acetate decreased the viability of SKOV-3 cells at 50 and 38 µg/mL, respectively, compared with CHO-K1 (>50 µg/mL) in MTT assays and generated changes in the cell morphology with apoptosis induction in Hemacolor® and TUNEL assays (p ≤ 0.05, ANOVA). The metabolite profile of AF02 showed a higher abundance of flavonoid and lipid compounds compared with AE by UPLC-MSE. Gallic acid and myricetin were the most active compounds in RHTR against SKOV-3 cells at 50 and 166 µg/mL, respectively (p ≤ 0.05, ANOVA). Antineoplastic studies in Nu/Nu female mice with subcutaneous SKOV-3 cells xenotransplant revealed that 200 mg/kg/i.p. of AE and AF02 inhibited ovarian tumor lesions from 37.6% to 49% after 28 days (p ≤ 0.05, ANOVA). In conclusion, RHTR has antineoplastic activity against ovarian cancer through a cytostatic effect related to gallic acid and myricetin. Therefore, RHTR could be a complementary treatment for this pathology.

Berberine exerts its antineoplastic effects by reversing the Warburg effect via downregulation of the Akt/mTOR/GLUT1 signaling pathway.

Glucose transporter 1 (GLUT1) plays a primary role in the glucose metabolism of cancer cells. However, to the best of our knowledge, there are currently no anticancer drugs that inhibit GLUT1 function. The present study aimed to investigate the antineoplastic activity of berberine (BBR), the main active ingredient in numerous Traditional Chinese medicinal herbs, on HepG2 and MCF7 cells. The results of Cell Counting Kit­8 assay, colony formation assay and flow cytometry revealed that BBR effectively inhibited the proliferation of tumor cells, and induced G2/M cell cycle arrest and apoptosis. Notably, the results of luminescence ATP detection assay and glucose uptake assay showed that BBR also significantly inhibited ATP synthesis and markedly decreased the glucose uptake ability, which suggested that the antitumor effect of BBR may occur via reversal of the Warburg effect. In addition, the results of reverse transcription­quantitative PCR, western blotting and immunofluorescence staining indicated that BBR downregulated the protein expression levels of GLUT1, maintained the cytoplasmic internalization of GLUT1 and suppressed the Akt/mTOR signaling pathway in both HepG2 and MCF7 cell lines. Augmentation of Akt phosphorylation levels by the Akt activator, SC79, abolished the BBR­induced decrease in ATP synthesis, glucose uptake, GLUT1 expression and cell proliferation, and reversed the proapoptotic effect of BBR. These findings indicated that the antineoplastic effect of BBR may involve the reversal of the Warburg effect by downregulating the Akt/mTOR/GLUT1 signaling pathway. Furthermore, the results of the co­immunoprecipitation assay demonstrated that BBR increased the interaction between ubiquitin conjugating enzyme E2 I (Ubc9) and GLUT1, which suggested that Ubc9 may mediate the proteasomal degradation of GLUT1. On the other hand, BBR decreased the interaction between Gα­interacting protein­interacting protein at the C­terminus (GIPC) and GLUT1, which suggested that the retention of GLUT1 in the cytoplasm may be achieved by inhibiting the interaction between GLUT1 and GIPC, thereby suppressing the glucose transporter function of GLUT1. The results of the present study provided a theoretical basis for the application of the Traditional Chinese medicine component, BBR, for cancer treatment.

Emodin - A natural anthraquinone derivative with diverse pharmacological activities.

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural anthraquinone derivative that is present in numerous globally renowned herbal medicines. It is recognised as a protein tyrosine kinase inhibitor and as an anticancer drug, active against various tumour cells, including lung, breast, liver, and ovarian cancer cells. Recently, its role in combination chemotherapy with various allopathic medicines, to minimize their toxicity and to enhance their efficacy, has been studied. The use of emodin in these therapies is gaining popularity, due to fewer associated side effects compared with standard anticancer drugs. Emodin has a broad therapeutic window, and in addition to its antineoplastic activity, it displays anti-ulcer, anti-inflammatory, hepatoprotective, neuroprotective, antimicrobial, muscle relaxant, immunosuppressive and antifibrotic activities, in both in vitro and in vivo models. Although reviews on the anticancer activity of emodin have been published, none coherently unite all the pharmacological properties of emodin, particularly the anti-oxidant, antimicrobial, antidiabetic, immunosuppressive and hepatoprotective activities of the compound. Hence, in this review, all of the available data regarding the pharmacological properties of emodin are explored, with particular emphasis on the modes of action of the molecule. In addition, the manuscript details the occurrence, biosynthesis and chemical synthesis of the compound, as well as its toxic effects on biotic systems.

Determination of in vitro antioxidant activity and in vivo antineoplastic effects against Ehrlich ascites carcinoma of methanolic extract of Sphagneticola calendulacea (L.) Pruski.

BACKGROUND AND AIM: Sphagneticola calendulacea (L.) Pruski (S. calendulacea) is a well-known medicinal plant that is widely used in traditional medicine. This study was conducted to evaluate the antioxidant and antineoplastic properties of S. calendulacea leaf. EXPERIMENTAL PROCEDURE: Methanol was used as a solvent to prepare leaf extract from the dried leaf of S. calendulacea (MESL). We have evaluated the total phenolic and flavonoid contents of MESL, and using five different assays; we have also evaluated the antioxidant property of MESL. In vivo antineoplastic activity of MESL against Ehrlich ascites carcinoma (EAC) cells in experimental mice was also explored. RESULTS: The phytochemical analysis of MESL exhibited the total phenolic, and total flavonoid contents in the dry extracts were 32.86 mg/gm of gallic acid equivalent and 127.26 mg/gm of catechin equivalent, respectively. Moreover, MESL also showed promising scavenging activity in all assays (IC50 value ≥70.5 µg/mL). In the in vivo antineoplastic assay, MESL showed increased EAC cell death at the doses of 50 mg/kg and 100 mg/kg body weight. MESL administration also induced apoptosis of EAC cells, significantly inhibited EAC cell growth, and increased the life span of EAC cell-bearing mice compared to EAC cell-bearing control mice. CONCLUSIONS: All findings of this study suggest potential antioxidant and antineoplastic properties of MESL.

Development and in vivo evaluation of fused benzazole analogs of anti-melanoma agent HA15.

Background: In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 (1) based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. Results: The structure-activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative (10b) exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound 10b induced a significant tumor growth inhibition in vivo with no apparent signs of toxicity. Conclusion: These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework.

Synthesis of pyrazoline fatty chain derivatives and its effects on melanoma cells.

Skin cancer is the most common type of cancer in Brazil, representing 30% of all cases. Among these, melanoma represents only 3% of malignant neoplasms; however, it is the most serious and has a high capacity for metastasis. For this reason, it is extremely important to identify more efficient compounds and treatments that stop or decrease the proliferation of melanoma, even in its more advanced stages. This work reports the synthesis and biological evaluation of two homologous series of pyrazoline fatty chain derivatives as potent antitumoral agents in the melanoma B16F10 cell line. Cells were treated with pyrazoline fatty chain compounds (3, 30, 300, and 3000 µM) for 0, 24, 48, and 72 h. Decreased cell viability was observed when using most compounds at different concentrations and times. The structure-activity relationship (SAR) between antitumoral activity and the number of carbons and lipophilicity, as well as the oxygen-sulfur bioisosteric exchange, was evaluated. Among the tested derivatives, the lipophilic compounds 5-hydroxy-5-(trifluoromethyl)-3-undecyl-4,5-dihydro-1H-pyrazole-1-carboxamide (2d) and 5-hydroxy-5-(trifluoromethyl)-3-undecyl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (3d) showed the best results in the B16F10 cell line, as they produced the best cell viability decrease effects. The presence of fatty unbranched undecyl chain in the molecular structure appears to be important for its antimelanoma properties.