lignans and cleistanthin

Cleistanthus collinus is an extremely toxic plant poison. We report a case of suicidal ingestion of boiled water decoction of C. collinus where the patient presented with abdominal pain and giddiness. There was persistent metabolic acidosis and fluctuation in the level of serum potassium. The ECG changes indicated a probable myocardial injury with conduction abnormality. At autopsy, the viscera were found to be congested. The toxins were detected in the viscera and blood by TLC and HPLC. Cleistanthin A and B, collinusin, and diphyllin are the principal toxic constituents of the plant. Consumption of a boiled decoction of leaves is highly toxic and, medical management of patients is mainly supportive because the molecular mechanisms of toxin action are unknown. In the recent years, C. collinus has created a considerable amount of interest because of its complex metabolites and their cytotoxic activities. Through this study, the authors have tried to highlight different properties pertaining to C. collinus.

Topics: Acidosis; Adult; Benzodioxoles; Euphorbiaceae; Female; Glycosides; Humans; Lignans; Naphthalenes; Plant Leaves; Suicide

We report the cases of two previously healthy young patients who ingested the liquid extracted from the crushed leaves of Cleistanthus collinus (Family: Euphorbiaceae) in an attempt to commit suicide. Both patients developed life threatening complications such as hypokalemia, hypotension, cardiac arrhythmias, neuromuscular weakness, respiratory failure, and renal failure following a transient quiescent period of up to 4 days. Other significant findings noted include leucocytosis, coagulopathy, elevated liver enzymes, hyperchloremic metabolic acidosis, and an alkaline urinary pH. Both patients received supportive care as no specific antidote was available, and ultimately died. We have reviewed the published literature on C. collinus poisoning.

Topics: Adult; Fatal Outcome; Female; Glycosides; Humans; Lignans; Plant Extracts; Suicide

The effect of Cleistanthin A was studied on isolated goat leg arteries using two different preparations namely transverse cylinder and longitudinal strip. The influence of Cleistanthin A on peripheral vascular resistance and myocardial contractility was evaluated by rat hind limb and isolated rat heart experiments, respectively. For the quantification of toxins, five different extracts of. Cleistanthin A increased vascular tension in transverse cylinder preparation and increased peak, trough and mean aortic pressures in the rat hind limb preparations. In isolated rat heart experiments, there was an increase in diastolic and mean ventricular pressure with a significant decrease in ventricular pulse pressure. These observations suggest that the hypotension in

Topics: Animals; Depression; Glycosides; Humans; Lignans; Rats; Vasoconstriction

Cleistanthin A (CleA), a natural diphyllin glycoside, has been shown to suppress the invasion of cancer cells, but the underlying mechanisms remain unclear. Here, the inhibitory effect of CleA on the invasion of MDA-MB-231 human breast cancer cells was investigated, and the mechanisms involved were clarified.. Cell viability was studied by MTT assay. The migration and invasion of MDA-MB-231 cells were assessed by wound healing assay and transwell assay, respectively. The enzymatic activity of matrix metalloproteinases (MMPs) was detected by gelatin zymography. mRNA and protein levels were detected by qRT-PCR and Western blotting, respectively. Nuclear translocation of β-catenin was observed by immunofluorescence and detected by Western blotting.. CleA effectively inhibited the migration and invasion of MDA-MB-231 cells and suppressed the expression and activation of MMP-2/9. Moreover, the expression and nuclear translocation of β-catenin were reduced by CleA treatment, as well as transcription of the Cyclin D1 and c-myc genes. In addition, the inhibitory effect of CleA on the β-catenin pathway was attributed to the promotion of β-catenin degradation by inhibition of GSK3β phosphorylation. When the phosphorylation of GSK3β was induced by LiCl, the inhibitory effect of CleA on the β-catenin pathway and the invasion of MDA-MB-231 cells were almost reversed.. CleA suppressed the invasion of MDA-MB-231 cells, likely through the β-catenin pathway.

Topics: Antineoplastic Agents, Phytogenic; beta Catenin; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Glycosides; Humans; Lignans; Matrix Metalloproteinases; Neoplasm Invasiveness

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Here, we investigated the molecular mechanisms that underpin the anticancer effects of cleistanthin A (CA) in two CRC cell lines, HCT 116, and SW480. At 48 h, CA exhibited apoptotic cytotoxic effects in both CRC cell lines, concomitant with reduction of an anti-apoptotic protein, survivin. Mechanistically, CA treatment significantly reduced the expression levels of β-catenin and active-β-catenin in a dose-dependent manner in both CRC cell lines. Moreover, CA suppressed the Wnt/β-catenin signaling pathway by decreasing β-catenin-mediated transcriptional activity and expression of β-catenin target genes, AXIN2, CCND1, and survivin. Furthermore, CA also inhibited transcriptional activity in cells overexpressing a constitutively active β-catenin S33Y, indicating a GSK-3β-independent mechanism underlying the observed CA effects on CRC cells. Although cytotoxic activity was not observed with CA treatment at 24 h, cell migration and invasion were significantly reduced. In addition, CA suppressed V-type ATPase activity and focal adhesion kinase (FAK) phosphorylation. Collectively, our study reveals that CA has time-dependent effects on CRC cell phenotypes. First, short-term CA treatment inhibited CRC cell migration and invasion partly through the suppression of V-type ATPase activity. This suppression resulted in reduced FAK activation. Second, longer-term CA treatment decreased cell viability which correlated with the suppression of Wnt/β-catenin signaling induced transcriptional activity. Altogether, our data suggest that CA has the potential to develop as an effective and novel therapeutic drug for CRC patients.

Topics: Apoptosis; Cell Movement; Colorectal Neoplasms; Dose-Response Relationship, Drug; Glycosides; HCT116 Cells; HEK293 Cells; Humans; Lignans; Neoplasm Invasiveness; Toxins, Biological; Wnt Signaling Pathway

Autophagy is a conserved lysosomal-dependent cellular degradation process and its dysregulation has been linked to numerous diseases including neurodegeneration, infectious diseases, and cancer. Modulation of autophagy is therefore considered as an attractive target for disease intervention. We carried out a high-content image analysis screen of natural product-derived compounds to discover novel autophagy modulating molecules. Our screen identified ECDD-S27 as the most effective compound for increasing the number of autophagic vacuoles inside cells. The structure of ECDD-S27 revealed that it is a derivative of cleistanthin A, a natural arylnaphthalene lignan glycoside found in plants. ECDD-S27 increases the number of autophagic vacuoles by inhibiting the autophagic flux and is able to restrict the survival of different cancer cells at low nanomolar concentrations. Molecular docking and SERS analysis showed that ECDD-S27 may potentially target the V-ATPase. Upon treatment of various cancer cells with ECDD-S27, the V-ATPase activity is potently inhibited thereby resulting in the loss of lysosomal acidification. Taken together, these data indicated that ECDD-S27 retards the autophagy pathway by targeting the V-ATPase and inhibits cancer cell survival. The observed antitumor activity without cytotoxicity to normal cells suggests the therapeutic potential warranting further studies on lead optimization of the compound for cancer treatment.

Topics: Animals; Antineoplastic Agents; Autophagosomes; Autophagy; Cell Survival; Glycosides; HeLa Cells; Hep G2 Cells; HT29 Cells; Humans; Lignans; Mice; RAW 264.7 Cells; Vacuolar Proton-Translocating ATPases

Novel lignan glycosides 1a-1 h as analogues of cleistanthin A were designed and synthesized. Most of these compounds displayed significant cytotoxicities against four cancer cell lines. Compound 1e displayed better cytotoxicity than cleistanthin A with IC50 values from 1.0 nm to 8.3 nm. Further lysosome acidity assay disclosed that 1e could totally inhibit the activity of V-ATPase at 60 nm.

Topics: Adenosine Triphosphatases; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Enzyme Activation; Glycosides; Humans; Inhibitory Concentration 50; Lignans; Molecular Structure

Twelve new glycosides and alkane derivatives of cleistanthin A were designed and synthesized. Their in vitro antiproliferative activity was investigated against HCT-116, HepG2, A549, Hela tumor cell lines and HEK293 cell by MTT assay. Most of these compounds displayed antiproliferative effects on four cancer cells at submicromolar concentration, but they were less potent than cleistanthin A Moreover, they showed no antiproliferative effects on HEK293 cell at 200 nm. The most potent compounds, 3e and 4a, have been shown to inhibit the activity of vacuolar H(+) -ATPase (V-ATPase) and neutralize the pH of lysosomes at submicromolar concentrations.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Glycosides; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Lignans; Lysosomes; Vacuolar Proton-Translocating ATPases

The vacuolar H(+)-ATPase (V-ATPase) was proposed as a key target for new strategies in cancer treatment recently. We have synthesized a novel class of derivatives of Cleistanthin-A bearing heterocyclic moieties. Most of these compounds displayed potent antiproliferative effects on four cancer cells at submicromolar concentration, and they have no cytotoxicity on normal WRL-68 cells at 200 nM. The most potent compound 3a has been shown to inhibit the activity of vacuolar H(+)-ATPase at submicromolar concentration, and it could also significantly decrease the cytosolic pH values in HepG2 cells. The current findings provide valuable insights for future development of novel V-ATPase inhibitors as anticancer agents.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Glycosides; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Lignans; Structure-Activity Relationship; Vacuolar Proton-Translocating ATPases

The concise syntheses of two natural diphyllin glycosides Cleistanthin-A (CA), Cleistanthoside-A (CleA) and its derivative, Cleistanthoside-A tetraacetate (CleT), have been achieved. They were evaluated for their in vitro anti-proliferative activities against MCF-7, HeLa, HepG2, HCT-116, U251 cancer cell lines by MTT assay. Both of CA and CleT were anti-proliferative to these cancer cells at nanomolar concentrations. They have been shown to inhibit the activity of vacuolar H(+)-ATPase (V-ATPase) in HepG2 cells and neutralize the pH of lysosomes at nanomolar concentrations.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Disaccharides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Glycosides; HCT116 Cells; HeLa Cells; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Lignans; Lysosomes; MCF-7 Cells; Molecular Conformation; Structure-Activity Relationship; Vacuolar Proton-Translocating ATPases

Cleistanthin A (CleinA) and cleistanthoside A (CleisA) isolated from plant Phyllanthus taxodiifolius Beille have previously shown potent anticancer effects. To promote their medicinal benefits, CleisA was modified to cleistanthoside A tetraacetate (CleisTA) and evaluated for genotoxic and anti-mutagenic properties in comparison with CleinA. Both compounds showed no significant mutagenic activity to S. typhimulium bacteria and no cytotoxic effect to normal mammalian cells. The non genotoxic effect of CleinA was further confirmed by un-alteration of cytokinesis-block proliferation index (CBPI) and micronucleus (MN) frequency assays in Chinese hamster lung fibroblast (V79) cells, and of CleisTA was confirmed by un-changes of human peripheral blood lymphocytes (HPBL) chromosomal structure assay. Moreover, the metabolic form of CleinA efficiently demonstrated cytostasis effect to V79 cell and prevented mutagen induced Salmonella TA98 and TA100 reversion, whereas both metabolic and non-metabolic forms of CleisTA reduced HPBL mitotic index (%M.I) in a concentration-dependent relationship. The results support CleinA and CleisTA as the new lead compounds for anti-cancer drug development.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cells, Cultured; Chromosome Aberrations; Cricetinae; Cricetulus; DNA Damage; Dose-Response Relationship, Drug; Fibroblasts; Glycosides; Humans; Lignans; Lung; Lymphocytes; Micronucleus Tests; Mitotic Index; Molecular Structure; Mutagens; Phyllanthus; Plant Components, Aerial; Salmonella typhimurium; Toxins, Biological

The arylnaphthalide lignan glycosides, taxodiifoloside, cleistanthoside A, cleistanthin A and cleistanthin A methyl ether, together with a triterpene, glochidone, have been isolated from the aerial parts of Phyllanthus taxodiifolius. The structures were established using spectral and chemical methods. Compounds and, as well as the derivatives and exhibited potent cytotoxic activities with GI50 values in the range of 10(-7)-10(-9) M in five cultured mammalian cancer cell lines while the new compound showed moderate activity (GI50 in the order of 10(-6) M). Compounds and were inactive in all tested cell lines.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line; Glucosides; Glycosides; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Phyllanthus; Plant Components, Aerial; Triterpenes

Cleistanthus collinus is an extremely toxic plant poison. Cleistanthin A and B, the toxins of Cleistanthus collinus, are diphyllin glycosides which produce cardiac arrhythmias, urinary potassium wasting, hypoxia, metabolic acidosis and hypotension. We report ARDS, distal renal tubular acidosis and distributive shock secondary to inappropriate vasodilatation in a case following ingestion of its leaves.

Topics: Acetylcysteine; Acidosis, Renal Tubular; Adult; Glycosides; Humans; Hypokalemia; Lignans; Male; Plant Leaves; Plant Poisoning; Plants, Toxic; Respiratory Distress Syndrome; Shock; Toxins, Biological; Treatment Outcome; Vasodilation

The study was conducted to determine the effects of boiled extract of Cleistanthus collinus on rats by observing ECG changes and electrolyte levels in serum and urine. Influence of minoxidil and glibenclamide on Cleistanthus collinus induced toxicity was determined. ED50 for arrhythmia, changes in contractility and heart rate were recorded using the isolated frog heart. Cleistanthus at low doses caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in rat. LD50 was found to be 1690 mg/kg. Minoxidil potentiated cardiac toxicity, whereas glibenclamide did not produce any significant change. High concentration of potassium in Cleistanthus extract hindered comparison of its levels. There was excretion of sodium even in the presence of hyponatraemia. Cleistanthus at low dose caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in isolated frog heart. ED50 for arrhythmia was found to be 1406 mg/kg. Acute toxicity was mainly due to depressive cardiac activity of Cleistanthus. It also caused renal failure. Potassium channel modulators did not have important role in acute cardiac toxicity treatment. Probably in chronic toxicity, electrolyte level changes are involved and potassium channel modulators might have a role.

Topics: Animals; Electrocardiography; Electrolytes; Female; Glyburide; Glycosides; Heart; Hydrogen-Ion Concentration; Lignans; Male; Minoxidil; Myocardium; Plant Extracts; Potassium; Potassium Channels; Ranidae; Rats; Rats, Wistar; Sodium; Time Factors; Trees

1. To study the clinical features in patients with Cleistanthus collinus poisoning, 2. To study in them the effect of Cleistanthus collinus poisoning on the various organ systems and metabolic parameters using standard laboratory investigations.. All patients admitted to the hospital between September 1998 and April 2000 were studied. Statistical analysis of the results was done using chi-square test, Fisher's exact test and Student's 't' test.. Forty six cases were studied, 15 (32%) of whom died. Eighty percent of the patients were in the second to third decade. The female:male ratio was 3:2. Ingestion of the poison as a decoction prepared from the leaves and ingestion of a large number of leaves otherwise were associated with a poor outcome. While survivors remained relatively asymptomatic, fatally poisoned patients presented with significant clinical signs and symptoms, however, laboratory abnormalities such as hypokalaemia, hyponatremia, an elevated AST/LDH/CPK/CPK-MB, nonspecific ST-T changes and QTc prolongation on ECG, metabolic acidosis and hypoxia with widened alveolar-arterial oxygen difference (A-aDO2) were seen in both groups.. It is a poisoning seen in the young with significant mortality. Cause of death appears to be mainly due to its cardiac and respiratory effects. Metabolic disturbances especially hypokalaemia was a prominent feature. Most deaths occurred on the 3rd day and all within a week. No specific antidote is available.

Topics: Adolescent; Adult; Aged; Female; Glycosides; Humans; India; Lignans; Male; Middle Aged; Naphthalenes; Plant Extracts; Poisoning; Survival Analysis; Toxins, Biological

Cleistanthin A is a novel anticancer agent isolated from Cleistanthus collinus (Rox B). It caused chromatid aberrations in a dose dependent manner. However, the concentrations that induced the aberrations, neither affected viability nor induced DNA strand breaks. Only at higher concentrations and after long exposure, DNA strand breaks were observed. Cleistanthin A induced apoptosis in Chinese hamster ovary (CHO) cells, in cervical carcinoma (Si Ha) cells and in a p53 deficient cell line K562. Cleistanthin A-induced cell death was low in bcl-2 transfected cells. Cleistanthin A inhibited the incorporation of [3H]thymidine into DNA; however, it did not affect the transport of [3H]thymidine into these cells. These studies indicate that the cytotoxic effects of cleistanthin A are mediated by the inhibition of DNA synthesis, induction of DNA damage and apoptosis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Survival; Chromatids; Chromosome Breakage; Cisplatin; Cricetinae; DNA; DNA Fragmentation; Dose-Response Relationship, Drug; Electrophoresis, Agar Gel; Female; Glucosides; Glycosides; Humans; Lignans; Proto-Oncogene Proteins c-bcl-2; Transfection

A diphyllin glycoside called cleistanthin A was isolated from the tropical plant Cleistanthus collinus and its anticancer potential was assessed. This compound showed preferential cytotoxicity in several tumor cell lines. The GI50 values for normal cell lines were between 10(-6) and 10(-7) M while for tumor cells the values ranged from 10(-7) to 10(-9) M. When the cytotoxicity of this compound was compared with five anticancer drugs, cleistanthin A was found to be most effective for the oral carcinoma cell line KB and the cervical carcinoma cell line SiHa. The efficacy of cleistanthin A in arresting tumor growth was assessed in mice harboring Dalton's ascites lymphoma and a solid tumor S-180 sarcoma. In both cases, the tumor volume was drastically reduced upon treatment with cleistanthin A. This compound also increased the life span of mice with S-180 sarcoma to a similar extent as that done by cisplatin (CDDP: cis-diamminedichloroplatinum) and etoposide. However, cleistanthin A was less toxic than these drugs because it did not affect the body weight and lymphocyte count in treated animals. Although the molecular mechanisms of action of cleistanthin A in arresting cell growth are yet to be explored in various perspectives, our present results indicate that this compound arrests growth by inhibiting DNA synthesis and cell division and by driving cells to apoptosis. Time-lapse video microscopic recordings of cleistanthin A-treated cells showed vigorous membrane blebbing, characteristic of apoptosis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Body Weight; Drug Screening Assays, Antitumor; Fibroblasts; Glycosides; Humans; Leukocytes; Lignans; Lymphocytes; Mice; Rats; Tumor Cells, Cultured

Enzyme-linked immunosorbent assay is reported for the estimation of cleistanthin A, a major constituent of the toxic plant Cleistanthus collinus. Rabbit antibodies were obtained by immunisation with cleistanthin A hemisuccinate-BSA conjugate and the ELISA developed thereupon could detect cleistanthin A at as low a concentration as 3 ng/ml. Cross-reactivity studies with structural analogs as well as with other phytotoxins and drugs of common occurrence established the suitability of the ELISA to specifically monitor the C. collinus marker molecules in emergency clinical and forensic cases. The simplicity and specificity make the ELISA superior to the other available techniques.

Topics: Cross Reactions; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; Glycosides; Humans; Lignans; Plant Poisoning; Plants, Toxic; Sensitivity and Specificity; Toxins, Biological

A method is reported for the solid-state fluorodensitometric determination of haptens in hapten-protein conjugates. The applicability of the method is shown using the bovine serum albumin conjugate of cleistanthin B, a toxic glycoside of the plant Cleistanthus collinus. This non-destructive technique, which is relatively simple, sensitive, rapid and versatile, can be used for the determination of protein conjugates of fluorogenic haptens.

Topics: Chromatography, Thin Layer; Glycosides; Haptens; Lignans; Plants, Toxic; Serum Albumin, Bovine; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet