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Cancer remains a significant global health concern, with mortality rates steadily rising and prompting an urgent search for effective treatments. This study focuses on the medicinal properties of plants from the Phyllanthus genus, specifically Phyllanthus amarus and Phyllanthus niruri, which have shown promise in traditional medicine. Through bioguided fractionation using preparative high-performance liquid chromatography (HPLC), bioactive compounds were isolated and identified using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UHPLC-QTOF-MS E ) and nuclear magnetic resonance (NMR) spectroscopy. Chemometric analyses such as principal component analysis (PCA) aided in understanding metabolite distribution. Biological assays demonstrated cytotoxic activities of specific fractions against cancer cell lines, notably the PhyN 4n fraction from P. niruri, which induced S-phase cell cycle arrest and apoptosis in HL60 cells. These findings underscore the anticancer potential of Phyllanthus species and lay the groundwork for future drug development efforts. The study's integration of advanced analytical techniques, chemometrics, and biological assays provides valuable insights for harnessing natural products in the fight against cancer., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The pentacyclic triterpene 3β,6β,16β-tri-hydroxilup-20(29)-ene is a natural product produced by the Brazilian medicinal plant Combretum leprosum. Its cytotoxicity has been previously reported against breast cancer cell lines. The low water solubility of this natural product, that hampers its bioavailability, motivated the investigation of a new nanoparticle formulation containing the triterpene in order to improve its bioactivity. The triterpene was encapsulated in polycaprolactone (PCL) polymer by nanoprecipitation, producing homogenic nanoparticles with nanometer sizes (122.7 ± 2.06 nm), which were characterized by FT-IR, SEM imaging and DSC. The cytotoxicity (MTT method) of the nanoparticle containing the triterpene 1, besides the free natural product and the nanoparticle control (without 1), was assayed against three human tumor cell lines [human colon carcinoma line (HCT116), prostate (PC3) and glioblastoma (SNB19)] and the normal epithelial embryo kidney human cell line (Hek293T). The nanocarrier produced a significative effect in the cytotoxicity of the natural product in the nanoformulation (IC 50 0.11-0.26 µg mL -1 ) when compared with its free form (IC 50 1.07-1.44 µg mL -1 ). Additionally, higher selectivity of the triterpene to the tumor cells was found when it was encapsulated (SI 1.92-4.54) than in its free form (SI 0.42-0.56). In this case, the nanoencapsulated triterpene was more selective to PC3 (SI 3.33) and SNB19 (SI 4.54) tumor cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Caatinga flora which are found in a poor Brazilian region contain a substantial number of endemic taxa with biomedical and social importance for regional communities. This study examined the antioxidant and cytotoxic potential of 35 samples (extracts/fractions) from 12 Caatinga species and determined the antiproliferative and genotoxic action of dichloromethane fraction from Mimosa caesalpiniifolia stem bark (DC-Mca) on human and vegetal cells. Samples were assessed for chemopreventive ability, toxic effects on Artemia salina shrimp as well as cytotoxicity on tumor cell lines and erythrocytes. DC-Mca was also tested with respect to antiproliferative and genotoxic effects upon normal leukocytes and meristematic cells from A. cepa roots. Some extracts reduced free radical levels >95% and 7 samples exhibited a lethal concentration (LC) 50  < 100 µg/ml upon Artemia salina larvae. Eight samples displayed in vitro antitumor effects and three produced hemolysis. Data also demonstrated the pharmacological significance of bioactive extracts from Brazilian semi-arid region. There was no significant relationship between antioxidant, toxic, and antiproliferative activities, and that these properties were dependent upon the extractant. DC-Mca contained betulinic acid as main compound (approximately 70%), which showed higher (1) cytotoxic activity on cancer cell lines and dividing leukocytes, (2) reduced mitotic index of Allium cepa roots, and (3) induced cell cycle arrest and chromosomal bridges, thereby providing native promising sources for phytotherapy development., Abbreviations: ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); AcOH: ethyl acetate; ANOVA: analysis of variance; SUS: Brazilian Unified Health System; DC-Mca: dichloromethane fraction from Mimosa caesalpiniifolia stem bark; DMSO: dimethylsulfoxide; DPPH: 1,1-diphenyl-2-picrylhydrazyl; EC 50 : effective concentration 50%; EtOAc: ethyl acetate; FDA: Food and Drug Administration; GC-Qms: gas chromatograph quadrupole mass spectrometer; GI: genotoxic index; HCT-116: colon carcinoma line; HL-60: promyelocytic leukemia line; HPLC: high-performance liquid chromatography; HRAPCIMS: high resolution atmospheric pressure chemical ionization mass spectrum; IC 50 : inhibitory concentration 50%; LC 50 : lethal concentration 50%; MeOH = methyl alcohol; MI: mitotic index; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; MutI: mutagenic index; OVCAR-8 = ovarian carcinoma line; PBMC: peripheral blood mononuclear cells; RPMI-1640: Roswell Park Memorial Institute medium; SF-295: glioblastoma line; TEAC: trolox equivalent antioxidant capacity; TLC: thin-layer chromatography; Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.

Ethnopharmacological Relevance: Extracts, essential oils and molecules from Casearia sylvestris have popularly shown pharmacological actions against chronic diseases, as anxiety, inflammation, cancer and dyslipidemia. In the context of antitumoral therapy, we investigated in vitro, ex vivo and in vivo toxicological changes induced by a Fraction with Casearins (FC) and its component Casearin X isolated from C. sylvestris on animal and vegetal cells, and upon invertebrates and mammals., Material and Methods: Cytotoxicity was carried out using normal lines and absorbance and flow cytometry techniques, Artemia salina nauplii, Danio rerio embryos and meristematic cells from Allium cepa roots. Acute and 30 days-mice analysis were done by behavioral, hematological and histological investigations and DNA/chromosomal damages detected by alkaline Cometa and micronucleus assays., Results: FC was cytotoxic against lung and fibroblasts cells and caused DNA breaks, loss of integrity and mitochondrial depolarization on ex vivo human leukocytes. It revealed 24 h-LC 50 values of 48.8 and 36.7 μg/mL on A. salina nauplii and D. rerio embryos, reduced mitotic index of A. cepa roots, leading to cell cycle arrest at metaphase and anaphase and micronuclei. FC showed i.p. and oral LD 50 values of 80.9 and 267.1 mg/kg body weight. Subacute i.p. injections induced loss of weight, swelling of hepatocytes and tubules, tubular and glomerular hemorrhage, microvesicular steatosis, lung inflammatory infiltration, augment of GPT, decrease of albumin, alkaline phosphatase, glucose, erythrocytes, and lymphocytes, and neutrophilia (p > 0.05). FC-treated animals at 10 mg/kg/day i.p. caused micronuclei in bone marrow and DNA strand breaks in peripheral leukocytes., Conclusions: This research postulated suggestive side effects after use of FC-related drugs, demonstrating FC as antiproliferative and genotoxic on mammal and meristematic cells, including human leukocytes, teratogenicity upon zebrafish embryos, myelosuppression, clastogenicity, and morphological and biochemical markers indicating liver as main target for FC-induced systemic toxicity., (Copyright © 2019. Published by Elsevier B.V.)

The use of natural products in therapeutics has been growing over the years. Lignans are compounds with large pharmaceutical use, which has aroused interest in the search for new drugs to treat diseases. The present study evaluated the cytotoxicity of (-)-trachelogenin, a dibenzylbutyrolactone type lignan isolated from Combretum fruticosum, against several tumor and non-tumor cell lines using the MTT assay and its possible mechanism of action. (-)-Trachelogenin showed IC 50 values ranging of 0.8-32.4μM in SF-295 and HL-60 cell lines, respectively and IC 50 values >64μM in non-tumor cell lines. (-)-trachelogenin persistently induced autophagic cell death, with cytoplasmic vacuolization and formation of autophagosomes mediated by increasing LC3 activation and altering the expression levels of Beclin-1., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Casearia sylvestris (Salicaceae) is found in South America and presents antiulcerogenic, cytotoxic, antimicrobial, anti-inflammatory and antihypertensive activities., Aim of the Study: To assess the in vivo and ex vivo antitumor action of a fraction with casearins (FC) and its main component - Casearin X-isolated from C. sylvestris leaves., Materials and Methods: Firstly, Sarcoma 180 bearing Swiss mice were treated with FC and Cas X for 7 days. Secondly, BALB/c nude animals received hollow fibers with colon carcinoma (HCT-116) or glioblastoma (SF-295) cells and were treated with FC for 4 days. On 5th day, proliferation was determined by MTT assay., Results: FC 10 and 25mg/kg/day i.p. and 50mg/kg/day oral and Cas X 25mg/kg/day i.p. and 50mg/kg/day oral revealed tumor growth inhibition rates of 35.8, 86.2, 53.7, 90.0 and 65.5% and such tumors demonstrated rare mitoses and coagulation necrosis areas. Similarly, FC reduced multiplying of HCT-116 and SF-295 cells when evaluated by the Hollow Fiber Assay (2.5 and 5mg/kg/day i.p. and 25 and 50mg/kg/day oral), with cell growth inhibition rates ranging from 33.3 to 67.4% (p<0.05). Flow cytometry experiments revealed that FC reduced membrane integrity and induced DNA fragmentation and mitochondrial depolarization (p<0.05)., Conclusions: FC and Cas X were efficient antitumor substances against murine and human cancer cells and caused reversible morphological changes in liver, kidneys and spleens, emphasizing clerodane diterpenes as an emerging class of anticancer molecules., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Endophytic actinobacteria from the Brazilian medicinal plant Lychnophora ericoides were isolated for the first time, and the biological potential of their secondary metabolites was evaluated. A phylogenic analysis of isolated actinobacteria was accomplished with 16S rRNA gene sequencing, and the predominance of the genus Streptomyces was observed. All strains were cultured on solid rice medium, and ethanol extracts were evaluated with antimicrobial and cytotoxic assays against cancer cell lines. As a result, 92% of the extracts showed a high or moderate activity against at least one pathogenic microbial strain or cancer cell line. Based on the biological and chemical analyses of crude extracts, three endophytic strains were selected for further investigation of their chemical profiles. Sixteen compounds were isolated, and 3-hydroxy-4-methoxybenzamide (9) and 2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone (15) are reported as natural products for the first time in this study. The biological activity of the pure compounds was also assessed. Compound 15 displayed potent cytotoxic activity against all four tested cancer cell lines. Nocardamine (2) was only moderately active against two cancer cell lines but showed strong activity against Trypanosoma cruzi. Our results show that endophytic actinobacteria from L. ericoides are a promising source of bioactive compounds., (© 2016 Verlag Helvetica Chimica Acta AG, Zürich.)

Biflorin is an o-naphthoquinone isolated from the roots of the plant Capraria biflora L. (Scrophulariaceae). In this study, the cytotoxic effects of biflorin were verified, and late apoptosis was detected in various cancer cell lines by in situ analysis. The cytotoxicity was further evaluated exclusively for 48 h of treatment in different tumor and non-tumor cell lines (Hep-2, HeLa, HT-29, A-375, and A-549, and HEK-293, respectively). The results indicated that biflorin induced selective cytotoxicity in tumor cells. HeLa cells were more susceptible to biflorin, followed by HT-29, A-549, A-375, and Hep-2 at all concentrations (range 5-50 μg/mL), and the highest half-maximal inhibitory concentration IC50 (56.01 ± 1.17 μg/mL) was observed in HEK-293 cells. Late apoptotic/necrotic events, observed by in situ immunostaining with Annexin V, varied with each cell line; an increase in late apoptotic events was observed corresponding to the increase in biflorin dosage. Hep-2 cells showed a greater percentage of late apoptotic events among the tumor cell lines when treated with higher concentrations of biflorin (69.63 ± 2.28%). The non-tumor HEK-293 line showed greater resistance to late apoptotic events, as well as a lower level of cytotoxicity (77.69 ± 6.68%) than the tested tumor lines. The data presented indicate that biflorin showed an important, possibly selective, cytotoxicity against tumor cell lines, thereby revealing a promising novel substance with potential anticancer activity for tumor therapy.

Mimosa caesalpiniifolia is a native plant of the Brazilian northeast, and few studies have investigated its chemical composition and biological significance. This work describes the identification of the first chemical constituents in the ethanolic extract and fractions of M. caesalpiniifolia stem bark based on NMR, GC-qMS and HRMS analyses, as well as an assessment of their cytotoxic activity. GC-qMS analysis showed fatty acid derivatives, triterpenes and steroid substances and confirmed the identity of the chemical compounds isolated from the hexane fraction. Metabolite biodiversity in M. caesalpiniifolia stem bark revealed the differentiated accumulation of pentacyclic triterpenic acids, with a high content of betulinic acid and minor amounts of 3-oxo and 3β-acetoxy derivatives. Bioactive analysis based on total phenolic and flavonoid content showed a high amount of these compounds in the ethanolic extract, and ESI-(-)-LTQ-Orbitrap-MS identified caffeoyl hexose at high intensity, as well as the presence of phenolic acids and flavonoids. Furthermore, the evaluation of the ethanolic extract and fractions, including betulinic acid, against colon (HCT-116), ovarian (OVCAR-8) and glioblastoma (SF-295) tumour cell lines showed that the crude extract, hexane and dichloromethane fractions possessed moderate to high inhibitory activity, which may be related to the abundance of betulinic acid. The phytochemical and biological study of M. caesalpiniifolia stem bark thus revealed a new alternative source of antitumour compounds, possibly made effective by the presence of betulinic acid and by chemical co-synergism with other compounds.

Piper tuberculatum, popularly known in Brazil as "jaborandi falso" and "pimenta darta", is widely used in folk medicine for the treatment of several diseases. In this study, the in vivo hollow fiber assay was used to investigate the antitumour efficacy of the crude extract and piplartine obtained from P. tuberculatum roots. Human glioblastoma (SF-295) and colon carcinoma (HCT-8) cell lines were used. In vitro cytotoxicity was assayed by the MTT assay. In the hollow fiber assay, nude mice implanted with tumour cells in hollow fibers were treated for four consecutive days via the intraperitoneal route, and tumour cell populations were assessed by the MTT assay. Both the crude extract and piplartine displayed cytotoxicity. In the hollow fiber assay, tumour growth inhibition rates were 24.6-54.8 % for the crude extract and 33.7-62.2 % for piplartine. No signal of toxicity was noticed. In conclusion, the crude extract and piplartine obtained from P. tuberculatum roots displayed in vitro and in vivo anticancer efficacy., (Georg Thieme Verlag KG Stuttgart · New York.)

Biflorin is an o-naphthoquinone with proven cytotoxic effects on tumor cells showing antimicrobial, antitumor and antimutagenic activities. Biflorin is an isolated compound taken from the roots of the plant Capraria biflora L. (Schrophulariaceae), indigenous of the West Indies and South America, which is located in temperate or tropical areas. This compound has shown to be strongly active against grampositive and alcohol-acid-resistant bacteria. It has been efficient in inhibiting the proliferation tumor cell lines CEM, HL-60, B16, HCT-8 and MCF-7. Recently, SK-Br3 cell line was treated with biflorin showing important cytotoxic effects. In this article, information related to the first structural characterization studies are presented, as well as the latest reports concerning the biological activity of this molecule.

Casearia sylvestris Swartz (Salicaceae) is a plant commonly widespread in the Americas. It has oxygenated tricyclic bioactive clerodane diterpenes with antimicrobial, antiulcer, larvicidal, chemopreventive, anti-inflammatory, antioxidant and antiproliferative properties. Due to this requirement for the developing of new anticancer drugs, it was initially evaluated the cytotoxic activity of a fraction with Casearins (FC) and its clerodane diterpenes Casearin B (Cas B), D (Cas D), X (Cas X) and Caseargrewiin F (Cas F) isolated from C.sylvestris leaves against 7 tumor cell lines, Sarcoma 180 cells (S180) and on normal peripheral blood mononuclear cells (PBMC). All substances tested showed cytotoxic potential. Cas F and X were the most active compounds. Cell death analyzes with Cas F (0.5 and 1μM) and Cas X (0.7 and 1.5μM) using the HL-60 leukemia line as experimental model showed DNA synthesis and membrane integrity reduction, DNA fragmentation and mitochondrial depolarization, specially after 24h exposure, cell cycle arrest in G0/G1 phase caused by Cas X, activation of the initiator -8/-9 and effector -3/-7 caspases and phosphatidylserine externalization, all biochemical features of apoptosis corroborated by chromatinic condensation, karyorrhexis, cytoplasmic vacuolation and rarefaction and cellular shrinkage, morphological findings specially observed after 12 and 24h of incubation. Therefore, Cas X and F were the most functional molecules with more pronounced lethal and discriminating effects on tumor cells and antiproliferative action predominantly mediated by apoptosis, highlighting clerodane dipertenes as promising lead antineoplastic compounds., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The aim of this study was to investigate the chemical composition and anticancer effect of the leaf essential oil of Xylopia frutescens in experimental models. The chemical composition of the essential oil was analysed by GC/FID and GC/MS. In vitro cytotoxic activity of the essential oil was determined on cultured tumour cells. In vivo antitumour activity was assessed in Sarcoma 180-bearing mice. The major compounds identified were (E)-caryophyllene (31.48%), bicyclogermacrene (15.13%), germacrene D (9.66%), δ-cadinene (5.44%), viridiflorene (5.09%) and α-copaene (4.35%). In vitro study of the essential oil displayed cytotoxicity on tumour cell lines and showed IC50 values ranging from 24.6 to 40.0 μg/ml for the NCI-H358M and PC-3M cell lines, respectively. In the in vivo antitumour study, tumour growth inhibition rates were 31.0-37.5%. In summary, the essential oil was dominated by sesquiterpene constituents and has some interesting anticancer activity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim: The aim of this study was to determine the antimetastatic potential of biflorin using in vivo and in vitro approaches., Main Methods: Biflorin was isolated from Capraria biflora collected in Fortaleza, Ceará, Brazil. Adhesion, migration and invasion assays were performed to avail of the antimetastatic potential of this quinone. Experimental metastasis was performed to avail of the antimetastatic potential of bilflorin using in vivo assay., Key Findings: Treatment with biflorin (25 and 50mg/kg/day) was shown to be effective in reducing B16-F10 melanoma metastasis in C57BL/6 mice. The administration of biflorin at 25mg/kg/day intraperitoneally inhibited the formation of metastases by about 57% compared to untreated control animals. When the animals were treated with 50mg/kg/day intraperitoneally, there was a 71% decrease in the number of lung metastases. Morphological assays showed the presence of hemosiderin and erythrocytes in the lung parenchyma, indicating the occurrence of hemorrhage, probably a side effect of biflorin. Biflorin at non-toxic concentrations (0.5, 1.0 and 1.5g/mL) was tested directly on B16-F10 cells in vitro, and it inhibited cell adhesion to type I collagen and cell motility using the wound-healing assay., Significance: These data suggest that biflorin has a promising antimetastatic potential, as shown by its anti-adhesion, anti-migration and anti-invasion properties against a metastatic melanoma cell line. However, further studies are essential to elucidate its mechanism of action., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Guatteria pogonopus Martius, a plant belonging to the Annonaceae family, is found in the remaining Brazilian Atlantic Forest. In this study, the chemical composition and antitumor effects of the essential oil isolated from leaves of G. pogonopus was investigated. The chemical composition of the oil was determined by GC-FID and GC/MS analyses. The in vitro cytotoxicity was evaluated against three different tumor cell lines (OVCAR-8, NCI-H358M, and PC-3M), and the in vivo antitumor activity was tested in mice bearing sarcoma 180 tumor. A total of 29 compounds was identified and quantified in the oil. The major compounds were γ-patchoulene (13.55%), (E)-caryophyllene (11.36%), β-pinene (10.37%), germacrene D (6.72%), bicyclogermacrene (5.97%), α-pinene (5.33%), and germacrene B (4.69%). The essential oil, but neither (E)-caryophyllene nor β-pinene, displayed in vitro cytotoxicity against all three tumor cell lines tested. The obtained average IC50 values ranged from 3.8 to 20.8 μg/ml. The lowest and highest values were obtained against the NCI-H358M and the OVCAR-8 cell lines, respectively. The in vivo tumor-growth-inhibition rates in the tumor-bearing mice treated with essential oil (50 and 100 mg/kg/d) were 25.3 and 42.6%, respectively. Hence, the essential oil showed significant in vitro and in vivo antitumor activity., (Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.)

Piplartine (piperlongumine, 5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)-pyridinone) is a biologically active alkaloid/amide from peppers, as from long pepper (Piper longum L. - Piperaceae). Long pepper is one of the most widely used in Ayurvedic medicine, which is used to treat many diseases, including tumors. The purpose of the current paper is to address to the chemical structure establishment and to systematically survey the published articles and highlight recent advances in the knowledge of the therapeutic potential of piplartine, establishing new goals for future research. The reported pharmacological activities of piplartine include cytotoxic, genotoxic, antitumor, antiangiogenic, antimetastatic, antiplatelet aggregation, antinociceptive, anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities. Among the multiple pharmacological effects of piplartine, its anticancer property is the most promising. Therefore, the preclinical anticancer potential of piplartine has been extensively investigated, which recently resulted in one patent. This compound is selectively cytotoxic against cancer cells by induction of oxidative stress, induces genotoxicity, as an alternative strategy to killing tumor cells, has excellent oral bioavailability in mice, inhibits tumor growth in mice, and presents only weak systemic toxicity. In summary, we conclude that piplartine is effective for use in cancer therapy and its safety using chronic toxicological studies should be addressed to support the viability of clinical trials., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Context: Cucurbitacins are a group of triterpenoids that have a cucurbitane skeleton with a wide range of biological activities., Objectives: This study evaluated the anticancer properties of one cucurbitacin isolated from Cayaponia racemosa Cong. (Cucurbitaceae), 2β,3β,16α,20(R),25-pentahydroxy-22-oxocucurbita-5-en (1), with in vitro and in vivo models., Materials and Methods: In vitro cytotoxic activity was determined with human leukemia (HL60) and normal blood cells (PBMC). Sarcoma 180 was used as in vivo model., Results: The cucurbitacin (1) reduced the number of viable cells; however, there was no changed in the number of non-viable cells at 5 µg/mL. Selectivity towards cancer cells was suggested by the absence of activity on normal proliferating lymphocytes at the concentrations tested (IC₅₀ >25 µg/ml). Morphological analysis of compound 1-treated cells showed typical apoptotic features, such as intense deposition of granules in the cytoplasm (eosinophilia), DNA fragmentation and irregularities in the plasma membrane. In addition, the cells treated with compound 1 presented intense vacuolization and disruption of the plasma membrane. Acridine orange/Ethidium bromide staining confirmed these findings, revealing an increased number of apoptotic cells. In the Sarcoma 180 tumor model, compound 1 showed 52 and 62% of antitumor activity, either alone (25 mg/kg/day) or in association with the chemotherapeutic agent 5-FU (10 + 10 mg/kg/day), respectively. Moreover, either alone or associated with 5-FU, treatment with compound 1 caused an increase in spleen weight and morphological alterations related to immunostimulatory properties., Conclusion: These data indicate that these naturally occurring compounds have anticancer potential.

Context: Quassinoids are biologically active secondary metabolites found exclusively in the Simaroubaceae family of plants. These compounds generally present important biological properties, including cytotoxic and antitumor properties., Objective: In the present study, the cytotoxic effects of neosergeolide, a quassinoid isolated from Picrolemma sprucei Hook. f., were evaluated in human promyelocytic leukemia cells (HL-60)., Materials and Methods: Cytotoxicity and antiproliferative effects were evaluated by the MTT assay, May-Grünwald-Giemsa's staining, BrdU incorporation test, and flow cytometry procedures. The comet assay and micronuclei analysis were applied to determine the genotoxic and mutagenic potential of neosergeolide., Results: After 24 h exposure, neosergeolide strongly inhibited cancer cell proliferation (IC₅₀ 0.1 µM), and its activity seemed to be selective to tumor cells because it had no antiproliferative effect on human peripheral blood mononuclear cells (PBMC) at tested concentrations. Apoptosis was induced at submicromolar concentrations (0.05, 0.1, and 0.2 µM) as evidenced by morphological changes, mitochondrial depolarization, phosphatidylserine externalization, caspases activation, and internucleosomal DNA fragmentation. Additionally, neosergeolide effects were prevented by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition (MPT) pore, which reinforced the participation of intrinsic pathways in the apoptotic process induced by this natural quassinoid. Direct DNA damage was further confirmed by comet assay and cytokinesis-block micronucleus test., Discussion and Conclusion: The present study provided experimental evidence to support the underlying mechanism of action involved in the neosergeolide-mediated apoptosis. In addition, no antiproliferative effect or DNA damage effect of neosergeolide was evident in PBMC, highlighting its therapeutic potential.

Guatteria friesiana (W. A. Rodrigues) Erkens & Maas (synonym Guatteriopsis friesiana W. A. Rodrigues), popularly known as "envireira", is a medicinal plant found in the Brazilian and Colombian Amazon basin that is used in traditional medicine for various purposes. Recent studies on this species have demonstrated antimicrobial activity. In this study, the antitumor activity of the essential oil from the leaves of G. friesiana (EOGF) and its main components ( α-, β-, and γ-eudesmol) were determined using experimental models. In the in vitro study, EOGF and its components α-, β-, and γ-eudesmol displayed cytotoxicity against tumor cell lines, showing IC₅₀ values in the range of 1.7 to 9.4 µg/mL in the HCT-8 and HL-60 cell lines for EOGF, 5.7 to 19.4 µg/mL in the HL-60 and MDA-MB-435 cell lines for α-eudesmol, 24.1 to > 25 µg/mL in the SF-295 and MDA-MB-435 cell lines for β-eudesmol, and 7.1 to 20.6 µg/mL in the SF-295 and MDA-MB-435 cell lines for γ-eudesmol, respectively. In the in vivo study, the antitumor effect of EOGF was evaluated in mice inoculated with sarcoma 180 tumor cells. Tumor growth inhibition rates were 43.4-54.2 % and 6.6-42.8 % for the EOGF treatment by intraperitoneal (50 and 100 mg/kg/day) and oral (100 and 200 mg/kg/day) administration, respectively. The treatment with EOGF did not significantly affect body mass, macroscopy of the organs, or blood leukocyte counts. Based on these results, we can conclude that EOGF possesses significant antitumor activity and has only low systemic toxicity. These effects could be assigned to its components α-, β-, and γ-eudesmol., (© Georg Thieme Verlag KG Stuttgart · New York.)

Folk uses and scientific investigations have highlighted the importance of Casearia sylvestris extracts and their relevant bioactive potential. The aim of this work was to review the pharmacological properties of C. sylvestris, emphasizing its anti-ulcer, anti-inflammatory, anti-ophidian and antitumor potentialities. Ethanolic extracts and essential oil of their leaves have antiulcerogenic activity and reduce gastric volume without altering the stomach pH, which corroborates their consumption on gastrointestinal disorders. Leaf water extracts show phospholipase A(2) inhibitory activity that prevents damage effects on the muscular tissue after toxin inoculation. This antiphospholipasic action is probably related to the use as an anti-inflammatory, proposing a pharmacological blockage similar to that obtained with non-steroidal anti-inflammatory drugs on arachidonic acid and cyclooxygenase pathways. Bioguided-assay fractionations lead to the identification of secondary metabolites, especially the clerodane diterpenes casearins (A-X) and casearvestrins (A-C), compounds with a remarkable cytotoxic and antitumor action. Therefore, the C. sylvestris shrub holds a known worldwide pharmacological arsenal by its extensive folk utilization, exciting searches for new molecules and a better comprehension about biological properties.

This study assessed the antiproliferative and cytotoxic potential against tumor lines of ethanolic seed extracts of 21 plant species belonging to different families from Northeastern Brazil. In addition, some underlying mechanisms involved in this cytotoxicity were also investigated. Among the 21 extracts tested, the MTT assay after 72 h of incubation demonstrated that only the ethanolic extract obtained from Myracrodruon urundeuva seeds (EEMUS), which has steroids, alkaloids and phenols, showed in vitro cytotoxic activity against human cancer cells, being 2-fold more active on leukemia HL-60 line [IC(50) value of 12.5 (9.5-16.7) μg/mL] than on glioblastoma SF-295 [IC(50) of 25.1 (17.3-36.3) μg/mL] and Sarcoma 180 cells [IC(50) of 38.1 (33.5-43.4) μg/mL]. After 72h exposure, flow cytometric and morphological analyses of HL-60-treated cells showed that EEMUS caused decrease in cell number, volume and viability as well as internucleosomal DNA fragmentation in a dose-dependent way, suggesting that the EEMUS triggers apoptotic pathways of cell death.

Ethnopharmacological Relevance: Himatanthus drasticus (Mart.) Plumel - Apocynaceae is a medicinal plant popularly known as Janaguba. Its bark and latex have been used by the public for cancer treatment, among other medicinal uses. However, there is almost no scientific research report on its medicinal properties., Aim of the Study: The aim of this study was to investigate the antitumor effects of Himatanthus drasticus latex proteins (HdLP) in experimental models., Materials and Methods: The in vitro cytotoxic activity of the HdLP was determined on cultured tumor cells. HdLP was also tested for its ability to induce lysis of mouse erythrocytes. In vivo antitumor activity was assessed in two experimental models, Sarcoma 180 and Walker 256 carcinosarcoma. Additionally, its effects on the immunological system were also investigated., Results: HdLP did not show any significant in vitro cytotoxic effect at experimental exposure levels. When intraperitoneally administered, HdLP was active against both in vivo experimental tumors. However, it was inactive by oral administration. The histopathological analysis indicates that the liver and kidney were only weakly affected by HdLP treatment. It was also demonstrated that HdLP acts as an immunomodulatory agent, increasing the production of OVA-specific antibodies. Additionally, it increased relative spleen weight and the incidence of megakaryocyte colonies., Conclusion: In summary, HdLP has some interesting anticancer activity that could be associated with its immunostimulating properties., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

In the search for new anti-cancer compounds, Brazilian Cerrado plant species have been investigated. The hexane root bark extract of Kielmeyera coriacea lead to a mixture of δ-tocotrienol (1) and its dimer (2). The structures of both compounds 1 and 2 were established based on detailed 1D and 2D NMR and EI-MS analyses. The cytotoxicity of the mixture was tested against four human tumor cell lines in the following cultures: MDA-MB-435 (melanoma), HCT-8 (colon), HL-60 (leukemia), and SF-295 (glioblastoma), and displayed IC(50) values ranging from 8.08 to 23.58μg/mL. Additional assays were performed in order to investigate the mechanism of action of the mixture (1+2) against the human leukemia cell line HL-60. The results suggested that the mixture suppressed leukemia growth and reduced cell survival, triggering both apoptosis and necrosis, depending on the concentration., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Latex of Calotropis procera has been described as a relevant source of pharmacologically active proteins, including proteins with anticancer activity. A previous in vitro study of laticifer proteins (LP) from C. procera reported that they had selective cytotoxic effects on human cancer cell lines. The aim of this study was to determine the effects of LP in vivo using mice transplanted with sarcoma 180. Biochemical, hematological, histopathological, and morphological analyses were performed in animals given LP by oral or intraperitoneal routes. LP significantly reduced tumor growth (51.83%) and augmented the survival time of animals for up to 4 days. Tumor growth inhibitory activity was lost when LP fraction was submitted to proteolysis, acidic treatment, or pretreated with iodoacetamide. However, LP retained its inhibitory activities on sarcoma 180 growth after heat treatment. Thus, it seems that heat-stable proteins are involved in tumor suppression. Biochemical parameters, such as the enzymatic activity of aspartate aminotransferase and alanine aminotransferase and urea content in serum were not affected in treated mice. It is worth noting that LP completely eliminated the 5-FU-induced depletion of leukocytes in mice even when given orally. The active proteins were recovered in a single fraction by ion exchange chromatography and still exhibited anticancer activity. This study confirms the pharmacological potential of proteins from the latex of C. procera to control sarcoma cell proliferation.

The cytotoxic potential of stem organic extracts from Calotropis procera (Asclepiadaceae) was firstly evaluated against cancer cell lines by MTT assay. Subsequently, samples considered cytotoxic were tested for antimitotic activity on sea urchin egg development and for in vivo antiproliferative activity in mice bearing Sarcoma 180 tumor. Among the five extracts (hexane, dichloromethane, ethyl acetate, acetone and methanol), ethyl acetate and acetone extracts displayed higher cytotoxic potential against tumor cells, with IC50 ranging from 0.8 to 4.4 microg/mL, while methanolic extract was weakly cytotoxic. Cytotoxic extracts also exhibited cell division inhibition capacity by antimitotic assay, revealing IC50 values lower than 5 microg/mL. In the in vivo antitumor assessments, ethyl acetate- and acetone-treated animals showed tumor growth inhibition ratios of 64.3 and 53.1%, respectively, with reversible toxic effects on liver and kidneys. Further studies are in progress in order to identify C. procera cytotoxic compound(s) and to understand the mechanism of action responsible for this tumor-decreasing potential.

Native and exotic Brazilian plants collected in the State of Minas Gerais were evaluated for their anticancer potential. Methanol extracts from leaves of 51 plant species were tested for cytotoxicity against four tumor cell lines: B16 (murine skin), HL-60 (human leukemia), MCF-7 (human breast), and HCT-8 (human colon). Plant extracts that exhibited IC(50) values less than 30 microg/ml against any tumor cell line were tested on sea urchin egg development and mouse erythrocytes. In addition, all extracts were evaluated for their general toxicity using the brine shrimp lethality assay. The most active extracts against the tumor cells were those obtained from Lantana fucata, Copaifera langsdorffii, and Momordica charantia. These three extracts inhibited sea urchin development from the first cleavage, but those from C. langsdorffii and M. charantia were very active against mouse erythrocytes. Only the L. fucata extract presented no hemolytic activity. Consequently, although the extracts of L. fucata, M. charantia, and C. langsdorffii could be useful in the development of new anticancer products, the first of these extracts is the most promising since it did not present unspecific toxicity, as suggested by negative results obtained with brine shrimp lethality and mouse erythrocytes assays.

The alkaloid extract and five alkaloids isolated from subterranean stem bark of Duguetia furfuracea (Annonaceae) were investigated for the following activities: antitumoral, trypanocidal and leishmanicidal. Dicentrinone showed weak cytotoxicity, but it had the strongest leishmanicidal activity (IC(50) 0.01 microM). Duguetine and duguetine beta-N-oxide caused considerable antitumoral activity in every cell lines evaluated, although duguetine was more active against trypomastigote forms (IC(50) 9.32 microM) than other alkaloids tested.

Two new diterpenes, 1 and 2, together with the known ent-15-oxo-kaur-16-en-18-oic acid (3), were isolated from the bark of Croton argyrophylloides. The structural characterization of 1 and 2 was determined on the basis of spectroscopic data interpretation. The cytotoxicity of each compound was evaluated against HL-60 (leukemia), MDAMB-435 (melanoma), SF-295 (glioblastoma), and HCT-8 (colon carcinoma) human tumor cell lines and against human peripheral blood mononuclear cells. The hemolytic potential in mouse erythrocytes was also tested for 1-3.

Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10alpha-acetoxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10alpha-hydroxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using alpha-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of alpha-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7alphaH,6betaH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7alphaH,6betaH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10alpha-acetoxy-3-oxo-1,7alphaH,6betaH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10alpha-acetoxy-3beta-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (10) and 3beta,10alpha-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC(50) values in the range of 0.36-14.5 microM, showed as common structural feature the presence of an alpha-methylidene-gamma-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development.

Croton regelianus Muell. Arg., popularly known as 'velame-de-cheiro', is a native plant from the Northeast of Brazil used in folk medicine to treat diseases of different kinds, including malignant tumors. In this study, the in vitro and in vivo antitumor effects of the essential oil from the leaves of C. regelianus and ascaridole, one of the main constituents, were investigated. In vitro, the essential oil and ascaridole displayed cytotoxicity, showing IC(50) values in the range of 22.2 to 48.0 microg/ml in HL-60 and SF-295 cell lines for the essential oil, and 6.3 to 18.4 microg/ml in HL-60 and HCT-8 cells lines for ascaridole, respectively. The in vivo study, using sarcoma 180 as a tumor model, demonstrated inhibition rates of 28.1 and 31.8% for essential oil, at the 50 and 100 mg/kg, while ascaridole inhibition rates were 33.9% at 10 mg/kg and 33.3% at 20-mg/kg doses. Histopathological examination showed that the organs were only weakly affected by the treatment. In conclusion, ascaridole has an interesting antitumor activity in sarcoma 180 murine model, probably related to the described cytotoxic activity, and, moreover, its presence in the essential oil from the leaves of C. regelianus could explain, at least in part, the ethnopharmacological use of this plant in the treatment of cancer.

Unlabelled: The search for new anti-cancer drugs is one of the most prominent research areas of natural products. Numerous active compounds isolated from Brazilian Cerrado plant species have been studied with promising results., Aim of the Study: To investigate the cytotoxic potential of 412 extracts from Brazilian Cerrado plants used in traditional medicine belonging to 21 families against tumor cell lines in culture., Material and Method: Maceration of 50 plant species resulted in 412 hexane, dichloromethane, ethanol and hydroalcohol extracts. The cytotoxicity of the extracts was tested against human colon carcinoma (HCT-8), melanoma (MDA-MB-435), and brain (SF-295) tumor cell lines, using the thiazolyl blue test (MTT) assay. Bioassay-guided fractionation was performed for one active extract., Results and Conclusions: Twenty-eight of the 412 tested extracts demonstrated a substantial antiproliferative effect, at least 85% inhibition of cell proliferation at 50 microg/mL against one or more cell lines. Those extracts are obtained from different parts of Anacardiaceae, Annonaceae, Apocynaceae, Clusiaceae, Flacourtiaceae, Sapindaceae, Sapotaceae, Simaroubaceae and Zingiberaceae. Complete dose-response curves were generated and IC(50) values were calculated for these active extracts against four cell lines HCT-8, MDA-MB-435, SF-295 and HL-60 (leukemia), and their direct cytotoxic effects were determined. In summary, 14 extracts of 13 species showed toxicity in all tested tumor cell lines, with IC(50) values ranging from 0.1 to 19.1 microg/mL. The strongest cytotoxic activity was found for the hexane extract of Casearia sylvestris var. lingua stem bark, with an IC(50) of 0.1 microg/mL for HCT-8, 0.9 microg/mL for SF-295, 1.2 microg/mL for MDA-MB-435, and 1.3 microg/mL for HL-60, and Simarouba versicolor root bark, with an IC(50) of 0.5 microg/mL for HCT-8, 0.7 microg/mL for SF-295, 1.5 microg/mL for MDA-MB-435, 1.1 microg/mL for HL-60. Bioassay-guided fractionation of the last extract led to the isolation of glaucarubinone, which showed pronounced activity against the four cell lines studied. Further studies of the active extracts are necessary for chemical characterization of the active compounds and more extensive biological evaluations.

Piplartine {5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propen-1-yl]-2(1H)-pyridinone} is an alkamide present in Piper species that exhibits promising anticancer properties. It was previously shown that piplartine is mutagenic in yeast and cultured mammalian cells. This study was performed to increase the knowledge on the mutagenic potential of piplartine using the Salmonella/microsome assay, V79 cell micronucleus and chromosome aberration assays, and mouse bone-marrow micronucleus tests. Piplartine was isolated from the roots of Piper tuberculatum. This extracted compound was unable to induce a mutagenic response in any Salmonella typhimurium strain either in the presence or absence of metabolic activation. Piplartine showed mutagenic effects in V79 cells, as there was an increased frequency of aberrant cells and micronuclei formation. In addition, piplartine administered at 50mg/kg did not induce micronucleus formation in vivo, but a dose of 100mg/kg induced an increase in the levels of micronucleus polychromatic erythrocytes (MNPCEs). Overall, these results provide further support that piplartine induces in vivo and in vitro mutagenicity in eukaryotic models.

As part of a bioprospecting program aimed at the discovery of potential anticancer drugs, two new guanidine-type alkaloids, nitensidines D and E (1, 2), and the known pterogynine (3), pterogynidine (4), and galegine (5), were isolated from the leaves of Pterogyne nitens. The structures of 1 and 2 were established on the basis of spectroscopic data interpretation. These compounds were tested against a small panel of human cancer cell lines. Compound 2 exhibited cytotoxicity for HL-60 (human myeloblastic leukemia) and SF-245 (human glioblastoma) cells.

Many authors have already emphasized that phytochemicals from spices have biological applications. Piperlonguminine is a known alkaloid amide from peppers, including Piper divaricatum. The aim of this study was to investigate the in vitro and in vivo antitumor effects of piperlonguminine in experimental models. In order to evaluate the toxicological aspects related to piperlonguminine treatment, hematological, biochemical, histopathological and morphological analyses of treated animals were performed. Piperlonguminine did not show any significant in vitro cytotoxic effect at experimental exposure levels, but showed an in vivo antitumor effect. After 7 days of treatment, the inhibition rates were 38.71% and 40.68% at doses of 25 mg kg(-1) and 50 mg kg(-1), respectively. The histopathological analysis suggests that the liver and kidney were only weakly affected by piperlonguminine treatment. Neither the enzymatic activity of transaminases (AST and ALT) nor the urea levels were significantly altered. In the hematological analysis, all parameters analysed remained constant after piperlonguminine treatment. In conclusion, these data reinforce the anticancer potential of spice components., (2008 John Wiley & Sons, Ltd)

This work evaluated the in vitro cytotoxic activity of laticifer proteins (LP) recovered from the latex of the medicinal plant Calotropis procera. The LP displayed considerable cytotoxicity with IC(50) values ranging from 0.42 to 1.36 microg/ml to SF295 and MDA-MB-435 cell lines, respectively. In healthy peripheral blood mononuclear cells exposed to LP (10 microg/ml) for 72 h, no noticeable effects on viability or cell morphology were seen. The fractionating of LP on an ion exchange chromatography gave rise to a new fraction (PI) that retained almost all cytotoxicity. The cytotoxic effects of both LP and PI were diminished when previously treated with pronase, or 2-mercaptoethanol, suggesting a protein nature of active molecules, however, pre-incubation with dithiothreitol (DTT) only reduced PI activity. PI did not exhibit cysteine proteinase activity, indicating that cysteine proteinases, abundantly found in LP, are not implicated in LP cytotoxicity. In this study, using HL-60 cell as a model, LP was shown to inhibit DNA synthesis. This is probably due to alterations in the topology of DNA, since it was observed that LP is able to interfere in topoisomerase I activity by somehow acting upon DNA. LP provoked reduction in cell number but it did not cause any significant increase in the number of non-viable cells. These findings corroborated with the morphologic analysis, where cells treated with LP showed morphology of apoptotic process with abundant vacuoles, chromatin condensation and fragmentation of the nuclei. The results of this study suggests that LP is a target for DNA topoisomerase I triggering apoptosis in cancer cell lines.

Pharmacological studies with an aqueous extract obtained from leaves of Capraria biflora showed potent cytotoxic, analgesic, antimicrobial and anti-inflammatory activities. It has been demonstrated that biflorin possesses an in vitro cytotoxic activity against tumor cells. The in vivo antitumor activity of biflorin was evaluated on two mouse models, sarcoma 180 and Ehrlich carcinoma. Biflorin was active against both tumors with a very similar profile. In addition, biflorin was also able to increase the response elicited by 5-FU in mice inoculated with both tumors. The results showed a decrease in Ki67 staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate. Histopathological analysis from kidneys and liver showed that biflorin possessed weak and reversible toxic effects. It was also demonstrated that biflorin acts as an immunoadjuvant agent, rising the production of ovalbumin-specific antibodies and inducing a discreet increase of the white pulp and nest of megakaryocytic in spleen of treated mice, which can be related to its antitumor properties.

Piplartine {5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)pyridinone} is an alkaloid/amide component of Piper species. The purpose of the present study was to examine the antiproliferative effects of piplartine on human leukemia cell lines HL-60, K562, Jukart, and Molt-4 using the trypan blue exclusion method, as well as the effect of piplartine on DNA synthesis. The viability of all human leukemia cell lines were not affected by piplartine after 6 h, 9 h, and 12 h exposure, whereas a steady decline was seen after an exposure time of 24 h. The antiproliferative activity of piplartine seemed to be related to the inhibition of DNA synthesis, as revealed by the reduction of 5-bromo-2'-deoxyuridine (BrdU) incorporation after 24h of incubation. Piplartine-mediated reduction in cell number was associated with an increasing number of dead cells at a concentration of 10 microg/ml. These findings were corroborated by morphologic analysis. However, at the lowest concentration (2.5 microg/ml), piplartine-treated cells exhibited typical apoptotic morphological changes. The increase in caspase-3 activity was also observed in lysates of piplartine-treated cells (2.5 microg/ml). Our findings suggest that piplartine can suppress leukemia growth and reduce cell survival, triggering both apoptosis and/or necrosis, depending on the concentration used.

Piplartine {5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)pyridinone} and piperine {1-5-(1,3)-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine} are alkaloid amides isolated from Piper. Both have been reported to show cytotoxic activity towards several tumor cell lines. In the present study, the in vivo antitumor activity of these compounds was evaluated in 60 female Swiss mice (N = 10 per group) transplanted with Sarcoma 180. Histopathological and morphological analyses of the tumor and the organs, including liver, spleen, and kidney, were performed in order to evaluate the toxicological aspects of the treatment with these amides. Administration of piplartine or piperine (50 or 100 mg kg(-1) day(-1) intraperitoneally for 7 days starting 1 day after inoculation) inhibited solid tumor development in mice transplanted with Sarcoma 180 cells. The inhibition rates were 28.7 and 52.3% for piplartine and 55.1 and 56.8% for piperine, after 7 days of treatment, at the lower and higher doses, respectively. The antitumor activity of piplartine was related to inhibition of the tumor proliferation rate, as observed by reduction of Ki67 staining, a nuclear antigen associated with G1, S, G2, and M cell cycle phases, in tumors from treated animals. However, piperine did not inhibit cell proliferation as observed in Ki67 immunohistochemical analysis. Histopathological analysis of liver and kidney showed that both organs were reversibly affected by piplartine and piperine treatment, but in a different way. Piperine was more toxic to the liver, leading to ballooning degeneration of hepatocytes, accompanied by microvesicular steatosis in some areas, than piplartine which, in turn, was more toxic to the kidney, leading to discrete hydropic changes of the proximal tubular and glomerular epithelium and tubular hemorrhage in treated animals.

(+)-2,3,9-Trimethoxy-pterocarpan (1) (+)-3,9-dimethoxy-pterocarpan [(+)-homopterocarpin] (2), (+)-3-hydroxy-9-methoxy-pterocarpan [(+)-medicarpin] (3) and (+)-3,4-dihydroxy-9-methoxy-pterocarpan [(+)-vesticarpan] (4) are cytotoxic pterocarpans isolated from the native Brazilian plant Platymiscium floribundum. The purpose of the present study was to examine whether induction of apoptosis and/or inhibition of DNA synthesis is involved in the cytotoxicity of these pterocarpans in human leukemia cells. The effect on cell viability determined using the trypan exclusion assay revealed that all compounds tested reduced the number of viable cells, while only in the presence of 3 and 4, there was an increase of nonviable cells. The analysis of membrane integrity and morphological modifications by flow cytometry in the presence of these two compounds indicated that treated cells undergo necrosis, while 1 and 2 trigger apoptosis. DNA synthesis seemed to be affected since BrdU incorporation was inhibited in a dose-dependent manner in the presence of all tested compounds. Pterocarpan treatment also induced an increase in the amount of subdiploid DNA, indicating internucleosomal DNA breakdown, mitochondrial depolarization and caspase-3 activation, which indicate apoptosis induction.

We have evaluated the in-vitro and in-vivo antitumour activity of physalin B and physalin D isolated from the aerial parts of Physalis angulata. In-vitro, both compounds displayed considerable cytotoxicity against several cancer cell lines, showing IC50 values in the range of 0.58 to 15.18 microg mL(-1) for physalin B, and 0.28 to 2.43 microg mL(-1) for physalin D. The antitumour activity of both compounds was confirmed in-vivo using mice bearing sarcoma 180 tumour cells. The in-vivo antitumour activity was related to the inhibition of tumour proliferation, as observed by the reduction of Ki67 staining in tumours of treated animals. Histopathological examination of the kidney and liver showed that both organs were affected by physalin treatment, but in a reversible manner. These compounds were probably responsible for the previously described antitumour activity of ethanol extracts of P. angulata, and their identification and characterization presented here could explain the ethnopharmacological use of this species in the treatment of cancer.

This study reports the antimitotic effects on sea urchin eggs of five known pterocarpans: (+)-3,10-dihydroxy-9-methoxypterocarpan, (+)-3,9-dimethoxypterocarpan [(+)-homopterocarpin], (+)-2,3,9-trimethoxypterocarpan, (+)-3,4-dihydroxy-9-methoxypterocarpan [(+)-vesticarpan] and (+)-3-hydroxy-9-methoxypterocarpan [(+)-medicarpin], isolated from the trunk of Platymiscium floribundum, a native tree from Brazil. All tested compounds showed strong activity in this assay, with 2,3,9-trimethoxypterocarpan being the most active (log IC50 of -8.10 +/- 0.02; -7.91 +/- 0.01; -7.97 +/- 0.02 M for first and third cleavages, and blastulae stages, respectively). These data suggest that the 2-methoxy substituent can be an important pharmacophoric unit.

The present study evaluated the anticancer potential of 11 plants used in Bangladeshi folk medicine. The extracts were tested for cytotoxicity using the brine shrimp lethality assay, sea urchin eggs assay, hemolysis assay and MTT assay using tumor cell lines. The extract of Oroxylum indicum showed the highest toxicity on all tumor cell lines tested, with an IC(50) of 19.6 microg/ml for CEM, 14.2 microg/ml for HL-60, 17.2 microg/ml for B-16 and 32.5 microg/ml for HCT-8. On the sea urchin eggs, it inhibited the progression of cell cycle since the frist cleavage (IC(50)=13.5 microg/ml). The extract of Aegle marmelos exhibited toxicity on all used assays, but in a lower potency than Oroxylum indicum. In conclusion, among all tested extracts, only the extracts of Oroxylum indicum, Moringa oleifera and Aegles marmelos could be considered as potential sources of anticancer compounds. Further studies are necessary for chemical characterization of the active principles and more extensive biological evaluations.

Two new isoflavonoids, 7-hydroxy-6,4'-dimethoxy-isoflavonequinone (1) and 2'-hydroxy-6,4',6' ',4' ''-tetramethoxy-[7-O-7' ']-bisisoflavone (2), and seven other known flavonoids, 3-hydroxy-9-methoxypterocarpan (medicarpin), 3,10-dihydroxy-9-methoxypterocarpan, 3,9-dimethoxypterocarpan (homopterocarpin) (3), 2,3,9-trimethoxypterocarpan (4), 3,4-dihydroxy-9-methoxypterocarpan (vesticarpan) (5), 2',4,4'-trihydroxychalcone (isoliquiritigenin), and 7,4'-dihydroxyflavanone (liquiritigenin) (6), were isolated from the heartwood of Platymiscium floribundum. The structures of compounds 1 and 2 were established by spectroscopic methods. Compounds 3-6 showed cytotoxic activity when evaluated against five human cancer cell lines in vitro.

(1a S*,1b S*,7a S*,8a S*)-4,5-Dimethoxy-1a,7a-dimethyl-1,1a,1b,2,7, 7a,8,8a-octahydrocyclopropa cyclopenta[1,2-b]naphthalene-3,6-dione (1), a new meroterpenoid benzoquinone, and microphyllaquinone (2), a known naphthoquinone, have been isolated from roots of Cordia globosa. Both structure determinations were performed by conventional spectroscopic methods, including inverse detection NMR techniques, and by comparison with data from the literature for related compounds. Compound 1 displayed considerable cytotoxic activity against several cancer cell lines with IC50 values in the range of 1.2 to 5.0 microg/mL. The cytotoxic activity seemed to be related to DNA synthesis inhibition, as revealed by the reduction of 5-bromo-2'-deoxyuridine incorporation, and apoptosis induction, as indicated by the acridine orange/ethidium bromide assay and morphological changes after 24 h of incubation on leukemic cells.

This work reports for the first time the production a furanoheliangolide (goyazensolide) by plant cell culture. Monitoring of the goyazensolide metabolism revealed that the maximum production occurred during the lag phase of the Lychnophora ericoides callus culture. The antiproliferative activity of obtained goyazensolide was evaluated against seven cancer cell lines using MTT assay. The results revealed a potent cytotoxic activity for the furaheliangolide with IC50 values in the range of 0.06 microg/ml for CEM leukemia cells to 0.75 microg/ml for B16 melanome cells.

The present study evaluated the cytotoxic activity of nepetin and quercetin-3-O-glucoside, compounds isolated from the aerial parts of Eupatorium ballotaefolium. The antimitotic activity was determined as the ability to inhibit sea urchin eggs development and five tumor cells lines growth. Moreover, the activities of these compounds were compared to quercetin in the same models. Nepetin inhibited the proliferation of the five tumor cell lines, once quercetin-3-O-glucoside did not present any activity even at the highest tested concentration and quercetin only inhibited proliferation of the B16 cell line. On the sea urchin assay, nepetin and quercetin induced a dose-dependent inhibition on egg development, while quercetin-3-O-glucoside did not modify normalegg cleavage, even at the highest tested concentration (100 microg/ml).

Phytochemical analysis of the leaves of Acnistus arborescens (Solanaceae) resulted in the isolation of two new epimeric withaphysalins (17S,20R,22R)-5beta,6beta: 18,20-diepoxy-4beta,18-dihydroxy-1-oxowitha-24-enolide (2, 18R and 18S), together with the known withaphysalin F (1, 18R and 18S). Their structures were established by spectroscopic methods, including 2D NMR data and comparison with literature data. Compounds 1 and 2 dis-played potent cytotoxic activities against several cancer cell lines with IC50 values in the range of 0.20 to 1.46 microg/mL for 1 and 0.89 to 8.08 microg/mL for 2. The strong cytotoxicity presented by 1 suggests that in this series of compounds, the 2,3-unsaturated ketone moiety is an important pharmacophoric unit. The cytotoxic activity seemed to be related to DNA synthesis inhibition, as revealed by the reduction of 5-bromo-2'-deoxyuridine incorporation after 24 hours of incubation on leukemic cells.

Five abietane diterpenes were isolated from a hexane extract obtained from the roots of Aegiphila lhotzkyana and identified as uncinatone, cyrtophyllone B, teunvicenone E, sugiol and 12,16-epoxy-11,14-dihydroxy-6-methoxy-17(15 - 16)- abeo-abieta-5,8, 11,13,15-pentaene-3,7-dione. The last compound has only been described for this species. These compounds were tested for their antiproliferative effects on tumor cell lines using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay and on sea urchin egg development, as well as for their lytic properties on mouse erythrocytes. All diterpenes reduced the viability of tumor cells and inhibited sea urchin egg cleavage. None of the tested compounds presented hemolytic activity.

Two abietane diterpenes were isolated from a hexane extract of Hyptis martiusii roots and identified as carnasol 11,14-dihidroxy-8,11,13-abietatrien-7-one. These compounds were tested for their antiproliferative effects on tumor cell lines using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and on the sea urchin egg development. Both compounds displayed cytotoxic activity against tumor cell lines, but only carnasol was able to inhibit the sea urchin egg cleavages.

Eleven known compounds and a new prenylated naphthoquinone, lippsidoquinone (13), were isolated from ethanol extracts of Lippia sidoides. Their structures were established by a combination of 1D and 2D NMR, IR, and EIMS spectral data analysis. The cytotoxic properties of compounds 3--13 were evaluated against HL60, SW1573, and CEM cell lines. Only tectol (6) and lippsidoquinone (13) exhibited significant activity against human leukemia cell lines HL60 and CEM.