DOCSLIB.ORG

Pharmaceutical Sciences

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmaceutical Sciences JOURNAL OF Pharmaceutical Sciences December 1967 volume 56, number 12 ___ Review Article __ Pharmacology and Toxicology of Toad Venom By K. K. CHEN and ALENA KOVARiKOVA CONTENTS speare made the witch throw a toad into the hell-broth. It has been long believed that han- HISTORY.. 1535 dling of toads causes warts. In a small area of CHEMICALINGREDIEXTSOF TOADPOISOX. 1536 Pharmacology of Bufadienolides. 1536 the state of Illinois, folklore has 300 references Bufagins. .... 1536 to warts of toad origin, particularly their cures (2). Bufotoxins. ... .. .. 1538 These superstitions can of course be disproved Clinical Trials... .... 1539 by laboratory experience. Houssay (3) op- Catecholamines. .. .. 1539 Epinephrine.. .. .. .. 1539 erated on 15,000 toads for endocrine studies and Norephinephrine.. .. .. .. .. 1539 we handled more than 10,000 toads for the Indolealkylamines..... 1539 collection of their poisons-with no ill effects. Noncardiotonic Sterols. .. 1540 In form of a votive animal, the toad is associated Cholesterol. ... .. .. ... .. .. 1540 with the uterus and various gynecological dis- Provitamin D. .. .. 1540 -v-Sitosterol .......... ... .. .. 1540 eases (4) in Central Europe. Bronze toads of Miscellaneous Substances.. 1540 the Perm culture of Kortheastern Russia were USE OF THE VENOMTO THE TOAD. 1540 among the archaeological findings dating from Protection from Enemies. 1540 the middle of the 1st century A.D. Significance to Behavior. 1540 ="ATURALTOLERANCETO CARDIACGLYCO- Toad medicine has been advocated all over SIDESANDAGLYCONES. 1540 the world. For many years the Chinese have RESPONSEOFOTHERTISSUESTODRUGS. 1541 used a preparation of toad venom, ch'an su, REFERENCES. 1541 for the treatment of canker sores, toothache, HISTORY sinusitis, and local inflammations (5). During the 15th century a European physician wrote a FOR CENTURIES the toad has been known to book, "De Vcnenis," in which he mentioned that produce a poisonous secretion. The Roman the toad's blood was of value in the treatment of women used the toad, although unsuccessfully, difficult breathing (6). Pharmacopeias and as a murdering agent for their unfaithful hus- dispensatories of early dates gave the dried toad bands (1). William Shakespeare, born about a prominent place among healing agents (7, 8). 400 years ago, pictured the toad as wearing a The South American Indians have made use of the precious jewel in its head.In Macbeth, Shake- skin secretion of the toad as arrow poison. These arrows are shot into game or enemies from blow- Received from the School of Medicine, Indiana University, tubes. Indianapolis, IN 46202 This investigation was supported in part by grant HE- The English word "toad" is applied to several 07714 from the U. S. Public Health Service, Bethesda, Md., and an Indiana Heart Association grant. tailless amphibians, but the various species under 1535 1536 Journal of Pharmaceutical Sciences discussion belong to the genus Bufo of the to Cn. They have a free secondary hydroxy Bufonidae family. The members of this genus group at Ca, and are known as bufagins cor- all have a pair of well-defined skin glands behind responding to aglycones of plants. The struc- the eyes, which secrete venom and are called tural formulas shown in Fig. 1 represent the "parotid" glands.The latter, however, have better known substances which are chemically no relation to salivary glands. The longitudinal bufadienolides (23) and synonymous with bufa- axis of the toad's parotid glands is parallel with gins. Because different species of toads do Hot the body axis, although that of exceptional synthesize identical bufadienolides, prefixes have species may be perpendicular to it-B. pelto- been employed for distinction. The Japanese cephaius and B. asper (9, 10). Additional glands toad apparently can produce all of them (24). may appear on arms and legs, e.g., B. alvarius In our laboratory gamabufagin and gamabufo- (11). The venom can be expressed from the talin are used interchangeably. parotid gland between the thumb and index N one of the bufadienolides in the toad venom finger, and into a glass evaporating dish held over conjugates with a carbohydrate to form a glyco- the toad's head. The toad has warts over the side, but a few couple with suberylarginine to dorsal part of the body, and their secretion is become bufotoxins. The first bufotoxin was difficult to obtain and mayor may not be identical isolated from the European common toad (25). with the parotid secretion. Vulpian (12, 13) dis- To distinguish it from other bufotoxins, Wieland's covered that the toad venom had a digitalis-like compound has been renamed vulgarobufotoxin action and that the toad's heart was relatively (26), and a structure of 14-suberylarginine bufo- immune to its own poison. The histology of talin has been proposed (22-27). Among the parotid glands and warts of European, South and amphibians, Bufo is the only genus elaborating North American toads has been documented by bufagins and bufotoxins (28). Recently it has several workers (14-16). been reported that a North African grasshopper, Ugly and venomous, one species of toads, Poekilocerus bufonius, feeding on milkweeds, is B. marinas, has saved sugar crops and other capable of storing glycosides of cardenolide type cultivated fields in the Hawaiian Islands and (29). Puerto Rico by devouring the insects which do Bufagins-The action of bufagins upon the damage to the plantations. Although the toad heart follows almost the same pattern as that of is reputed to enjoy longevity, it lives in the digitalis glycosides. Perfusion by various methods laboratory from 8.5 to almost 16 years (17). with appropriate concentrations in the frog Attempts to isolate pharmacologically active results in systolic standstill. The absorption substances from the European common toad is generally poor. The positive inotropic action were initiated over a half century ago (18). is easily demonstrated in mammals, such as the Abel and Macht (8) succeeded in isolating "bufa- cat, by slow infusion of a dilute solution of gin" and epinephrine from the parotid venom of regularobufagin.Electrocardiographic changes B. marinus. This was followed by the eventual are most instructive. Figure 2 serves as an identification of bufotalin and bufotoxin from example. The prolongation of P-R interval, B. bufo bufo by Wieland and Weil (19) and cino- bradycardia, the diphasic T-wave, the nodal bufagin and cinobufotoxin from ch'an su (20). rhythm, the A-V dissociation, and the idio- Marked advances were made at the University of ventricular rhythm are obvious. The slowing of Basel (21, 22), for numerous cardioactive sub- heart rate can be abolished by atropinization but stances were isolated from ch'an su, and later not by vagotomy. The effect of bufagins on the from the venoms of other species by elegant heart is less cumulative than that of digitoxin, modern methods. It is now clear that the being more like that of ouabain. There is a low chemical composition of the venom of each order of absorption through the gastrointestinal species of Bufo differs from one another, although tract in mammals. Thus, no more than 15% there are many similarities. Most species of cinobufagin is absorbed by oral administration elaborate in addition, noncardiotonic sterols, in anesthetized cats, and 50% of bufalin (36) indolealkylamines, and several, catecholamines. by intrajejunal injection in nonanesthetized dogs. CHEMICAL INGREDIENTS OF TOAD VENOM Because the chemical structures of bufagins differ from one another, their cardiac activity Pharmacology of Bufadienolides varies. Table I shows the potencies of 27 com- The cardia active sterols are naturally the pounds. Their mean (geometric) lethal doses center of interest. In all instances the lactone (LD's) are determined in groups of 10 or more ring is 6-membered of a-pyrone type, attached etherized cats. It should be noted that bufota- / Vol. 56, No. 12, December 1967 1537 ,co co co IA IA A t OH OH OAe .OH ~ ~ ~ HO H HO H HO ~H BUFALIN BUFOTALIN TELOCINOBUFAGIN co HCOrt--P° HO.. 1 A OH ~ ~ HO H HO HO OH BUFOTALIDIN GAMABUFOTALIN ARENOBUFAGIN Fig. l-Structural [orrnu- las jor better known sub- stances which are chemi- caliybufadenolides (23) and O'CO O'CO 0 synonymous with bujagins. IA IA rt--P o o ~OAC ~ HO~ H HO OH HO H RESIBUFOGENIN MARINOBUFAGIN CINOBUFAGIN (O,~O O'CO O° IA HCO o o OAe ~ ~ HO HO H HO OH ?OH DESACETYLCINOBUFAGIN BUFOTALININ CINOBUFOTALIN plant ongm is exemplified by several species (37-39). When the means are converted to their reciprocals, they become the number of t + 1., . -I,: I.. !: LD's:per mg. as given in Table I, expressing the I • direct relationship of activity. The very high potency (toxicity) of some of these substances t • _' I ! ! I IL I 1 ---L_ L 1 1 J ' can be appreciated if one realizes that 1 Gm. of , I' i : t I'," 11" , t I I acetyl bufotalidin may have 15,600 cat LD's. The contributions of the Basel scholars make ,:~~Vr-t·:i it possible to arrive at certain trends of structure- activity relationship (30). If we consider bu- falin the simplest bufadienolide, substitution of H with 5!J-OH in telocinobufagin, or with lla- OH in gamabufagin increases the activity (Table I).A 12-keto group in arenobufagin further enhances the activity.The presence of a free 16-0H in desacetyl bufotalin reduces the toxicity, but 16-acetyl in bufotalin brings back the potency of bufalin. In other cases, 16-desacetyla- tion abolishes the cardiac effect of cinobufagin Fig. 2-Electrocardiographic changes induced by and cinobufotalin. 3-Acetylation of cinobufo- regularobujagin in a cat. Regularobujagin 'in per- talin, marinobufagin, and bufotalidin (helle- cent oj jatal dose (top to bottom): 0, 57, 60, 67, 99. brigenin) has a favorable influence on the po- tency to various degrees, but the same reaction lidin is identical with hellebrigenin, an aglycone with cinobufagin produces the opposite effect.
Load more

Recommended publications
  • Bufadienolides from the Skin Secretions of the Neotropical Toad Rhinella Alata (Anura: Bufonidae): Antiprotozoal Activity Against Trypanosoma Cruzi
    molecules Article Bufadienolides from the Skin Secretions of the Neotropical Toad Rhinella alata (Anura: Bufonidae): Antiprotozoal Activity against Trypanosoma cruzi Candelario Rodriguez 1,2,3 , Roberto Ibáñez 4 , Luis Mojica 5, Michelle Ng 6, Carmenza Spadafora 6 , Armando A. Durant-Archibold 1,3,* and Marcelino Gutiérrez 1,* 1 Centro de Biodiversidad y Descubrimiento de Drogas, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Apartado 0843-01103, Panama; [email protected] 2 Department of Biotechnology, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India 3 Departamento de Bioquímica, Facultad de Ciencias Naturales, Exactas y Tecnología, Universidad de Panamá, Apartado 0824-03366, Panama 4 Smithsonian Tropical Research Institute (STRI), Balboa, Ancon P.O. Box 0843-03092, Panama; [email protected] 5 Centro Nacional de Metrología de Panamá (CENAMEP AIP), Apartado 0843-01353, Panama; [email protected] 6 Centro de Biología Celular y Molecular de Enfermedades, INDICASAT AIP, Apartado 0843-01103, Panama; [email protected] (M.N.); [email protected] (C.S.) * Correspondence: [email protected] (A.A.D.-A.); [email protected] (M.G.) Abstract: Toads in the family Bufonidae contain bufadienolides in their venom, which are charac- Citation: Rodriguez, C.; Ibáñez, R.; terized by their chemical diversity and high pharmacological potential. American trypanosomiasis Mojica, L.; Ng, M.; Spadafora, C.; is a neglected disease that affects an estimated 8 million people in tropical and subtropical coun- Durant-Archibold, A.A.; Gutiérrez, M. tries. In this research, we investigated the chemical composition and antitrypanosomal activity Bufadienolides from the Skin of toad venom from Rhinella alata collected in Panama.
    [Show full text]
  • Preventive and Therapeutic Effects of Chinese Herbal Compounds Against Hepatocellular Carcinoma
    molecules Review Preventive and Therapeutic Effects of Chinese Herbal Compounds against Hepatocellular Carcinoma Bing Hu 1,*, Hong-Mei An 2, Shuang-Shuang Wang 1, Jin-Jun Chen 3 and Ling Xu 1 1 Department of Oncology and Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; [email protected] (S.-S.W.); [email protected] (L.X.) 2 Department of Science & Technology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China; [email protected] 3 Department of Plastic & Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, The Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China; [email protected] * Correspondence: [email protected]; Tel.: +86-21-64385700 Academic Editor: Derek J. McPhee Received: 16 November 2015 ; Accepted: 20 January 2016 ; Published: 27 January 2016 Abstract: Traditional Chinese Medicines, unique biomedical and pharmaceutical resources, have been widely used for hepatocellular carcinoma (HCC) prevention and treatment. Accumulated Chinese herb-derived compounds with significant anti-cancer effects against HCC have been identified. Chinese herbal compounds are effective in preventing carcinogenesis, inhibiting cell proliferation, arresting cell cycle, inducing apoptosis, autophagy, cell senescence and anoikis, inhibiting epithelial-mesenchymal transition, metastasis and angiogenesis, regulating immune function, reversing drug
    [Show full text]
  • Cinobufagin Inhibits Tumor Growth by Inducing Apoptosis Through Notch Signaling Pathways in Human Cholangiocarcinoma
    2469 Original Article Cinobufagin inhibits tumor growth by inducing apoptosis through Notch signaling pathways in human cholangiocarcinoma Jiajun Ren1, Shouhua Wang2, Longyang Jin2, Fei Ma3, Di Zhou2, Qiang Cai1 1Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; 2Department of General Surgery, 3Department of Oncology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China Contributions: (I) Conception and design: J Ren, D Zhou, Q Cai; (II) Administrative support: D Zhou, Q Cai; (III) Provision of study materials or patients: S Wang, L Jin; (IV) Collection and assembly of data: S Wang, F Ma; (V) Data analysis and interpretation: L Jin, F Ma; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Qiang Cai. Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin No. 2 Road, Shanghai 200025, China. Email: [email protected]; Di Zhou. Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Email: [email protected]. Background: Many studies have shown that cinobufagin has antitumor effects against many cancers. The aim of this study was to assess the effects of cinobufagin on cholangiocarcinoma (CCA) cells. Methods: Colony formation assay, cell-counting kit-8 (CCK-8) assay, and tumor xenograft experiments were applied to investigate the function of cinobufagin on human CCA cells, in vitro and in vivo. Flow cytometric analysis was performed to validate the effects of cinobufagin on cell apoptosis.
    [Show full text]
  • Toxicology in Antiquity
    TOXICOLOGY IN ANTIQUITY Other published books in the History of Toxicology and Environmental Health series Wexler, History of Toxicology and Environmental Health: Toxicology in Antiquity, Volume I, May 2014, 978-0-12-800045-8 Wexler, History of Toxicology and Environmental Health: Toxicology in Antiquity, Volume II, September 2014, 978-0-12-801506-3 Wexler, Toxicology in the Middle Ages and Renaissance, March 2017, 978-0-12-809554-6 Bobst, History of Risk Assessment in Toxicology, October 2017, 978-0-12-809532-4 Balls, et al., The History of Alternative Test Methods in Toxicology, October 2018, 978-0-12-813697-3 TOXICOLOGY IN ANTIQUITY SECOND EDITION Edited by PHILIP WEXLER Retired, National Library of Medicine’s (NLM) Toxicology and Environmental Health Information Program, Bethesda, MD, USA Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright r 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
    [Show full text]
  • Rope Parasite” the Rope Parasite Parasites: Nearly Every AuSC Child I Ever Treated Proved to Carry a Significant Parasite Burden
    Au#sm: 2015 Dietrich Klinghardt MD, PhD Infec4ons and Infestaons Chronic Infecons, Infesta#ons and ASD Infec4ons affect us in 3 ways: 1. Immune reac,on against the microbes or their metabolic products Treatment: low dose immunotherapy (LDI, LDA, EPD) 2. Effects of their secreted endo- and exotoxins and metabolic waste Treatment: colon hydrotherapy, sauna, intes4nal binders (Enterosgel, MicroSilica, chlorella, zeolite), detoxificaon with herbs and medical drugs, ac4vaon of detox pathways by solving underlying blocKages (methylaon, etc.) 3. Compe,,on for our micronutrients Treatment: decrease microbial load, consider vitamin/mineral protocol Lyme, Toxins and Epigene#cs • In 2000 I examined 10 au4s4c children with no Known history of Lyme disease (age 3-10), with the IgeneX Western Blot test – aer successful treatment. 5 children were IgM posi4ve, 3 children IgG, 2 children were negave. That is 80% of the children had clinical Lyme disease, none the history of a 4cK bite! • Why is it taking so long for au4sm-literate prac44oners to embrace the fact, that many au4s4c children have contracted Lyme or several co-infec4ons in the womb from an oVen asymptomac mother? Why not become Lyme literate also? • Infec4ons can be treated without the use of an4bio4cs, using liposomal ozonated essen4al oils, herbs, ozone, Rife devices, PEMF, colloidal silver, regular s.c injecons of artesunate, the Klinghardt co-infec4on cocKtail and more. • Symptomac infec4ons and infestaons are almost always the result of a high body burden of glyphosate, mercury and aluminum - against the bacKdrop of epigene4c injuries (epimutaons) suffered in the womb or from our ancestors( trauma, vaccine adjuvants, worK place related lead, aluminum, herbicides etc., electromagne4c radiaon exposures etc.) • Most symptoms are caused by a confused upregulated immune system (molecular mimicry) Toxins from a toxic environment enter our system through damaged boundaries and membranes (gut barrier, blood brain barrier, damaged endothelium, etc.).
    [Show full text]
  • Salmonella Typhimurium, the Major Causative Agent of Foodborne
    Salmonella Typhimurium, the major causative agent of foodborne illness inactivated by a phage lysis system provides effective protection against lethal challenge by induction of robust cell-mediated immune responses and activation of dendritic cells Gayeon Won, John Hwa Lee To cite this version: Gayeon Won, John Hwa Lee. Salmonella Typhimurium, the major causative agent of foodborne illness inactivated by a phage lysis system provides effective protection against lethal challenge by induction of robust cell-mediated immune responses and activation of dendritic cells. Veterinary Research, BioMed Central, 2017, 48 (1), pp.66. 10.1186/s13567-017-0474-x. hal-01623956 HAL Id: hal-01623956 https://hal.archives-ouvertes.fr/hal-01623956 Submitted on 25 Oct 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Won and Lee Vet Res (2017) 48:66 DOI 10.1186/s13567-017-0474-x RESEARCH ARTICLE Open Access Salmonella Typhimurium, the major causative agent of foodborne illness inactivated by a phage lysis system provides efective protection against lethal challenge by induction of robust cell‑mediated immune responses and activation of dendritic cells Gayeon Won and John Hwa Lee* Abstract Salmonella Typhimurium infection via foodborne transmission remains a major public health threat even in devel- oped countries.
    [Show full text]
  • The Impact of Multiple Climatic and Geographic Factors on the Chemical Defences of Asian Toads (Bufo Gargarizans Cantor)
    www.nature.com/scientificreports OPEN The impact of multiple climatic and geographic factors on the chemical defences of Asian toads (Bufo gargarizans Cantor) Yueting Cao, Keke Cui, Hongye Pan, Jiheng Wu & Longhu Wang* Chemical defences are widespread in nature, yet we know little about whether and how climatic and geographic factors afect their evolution. In this study, we investigated the natural variation in the concentration and composition of the main bufogenin toxin in adult Asian toads (Bufo gargarizans Cantor) captured in twenty-two regions. Moreover, we explored the relative importance of eight climatic factors (average temperature, maximum temperature, minimum temperature, average relative humidity, 20–20 time precipitation, maximum continuous precipitation, maximum ground temperature, and minimum ground temperature) in regulating toxin production. We found that compared to toads captured from central and southwestern China, toads from eastern China secreted higher concentrations of cinobufagin (CBG) and resibufogenin (RBG) but lower concentrations of telocinobufagin (TBG) and cinobufotalin (CFL). All 8 climatic variables had signifcant efects on bufogenin production (ri>0.5), while the plastic response of bufogenin toxin to various climate factors was highly variable. The most important climatic driver of total bufogenin production was precipitation: the bufogenin concentration increased with increasing precipitation. This study indicated that the evolution of phenotypic plasticity in chemical defences may depend at least partly on the geographic variation of defensive toxins and their climatic context. Chemical defences is ubiquitous in nature and can serve for deterring predators, competitors, parasites, and path- ogens1–3. Many species can secrete a large diversity of toxic defensive compounds for self-protection.
    [Show full text]
  • Cinobufagin-Induced DNA Damage Response Activates G2/M Checkpoint and Apoptosis to Cause Selective Cytotoxicity in Cancer Cells
    Cinobufagin-Induced DNA Damage Response Activates G2/M Checkpoint and Apoptosis to Cause Selective Cytotoxicity in Cancer Cells Jiajing Niu Jilin University Jiamei Wang Jilin University Qi Zhang Jilin University Second Hospital Zhihua Zou ( [email protected] ) Jilin University https://orcid.org/0000-0003-4307-6788 Yushuang Ding Jilin University Second Hospital Research Article Keywords: cinobufagin, ROS, oxidative DNA damage, DNA damage response, cell cycle arrest, apoptosis Posted Date: June 1st, 2021 DOI: https://doi.org/10.21203/rs.3.rs-564587/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/25 Abstract Background: Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood. Methods: Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and ow cytometry, and DNA damage was analyzed by immunouorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by ow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane poten tial assays. Results: Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specic increase in cellular ROS and was signicantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity.
    [Show full text]
  • Cinobufagin, a Bufadienolide, Activates ROS-Mediated Pathways to Trigger Human Lung Cancer Cell Apoptosis in Vivo
    RSC Advances View Article Online PAPER View Journal | View Issue Cinobufagin, a bufadienolide, activates ROS- mediated pathways to trigger human lung cancer Cite this: RSC Adv.,2017,7,25175 cell apoptosis in vivo† Panli Peng, ab Junhong Lv,c Changqing Cai,b Shaohuan Lin,c Enqing Zhuob and Senming Wang*a Lung cancer, as the most common malignancy worldwide, is one of the most threatening diseases for human beings. Chan Su, an ethanolic extract from skin and parotid venom glands of the Bufo bufo gargarizans Cantor, is widely used as a traditional Chinese medicine in cancer therapy. Bufadienolides are cardiotonic steroids isolated from the skin and parotid venom glands of toad Bufo bufo gargarizans Cantor with excellent anticancer activity. Unfortunately, little information about the in vivo effects and action mechanisms of bufadienolides on human lung cancer cells is available. Therefore, in this study, the anticancer activities of Cinobufagin (CnBu), bufalin (Bu) and arenobufagin (ArBu) were evaluated in Creative Commons Attribution 3.0 Unported Licence. vivo and in vitro and the underlying mechanisms were elucidated. The results showed that CnBu exhibited higher anticancer efficacy than Bu and AuBu against a panel of five lung cancer cells (A549, NCI-H460, H1299, Sk-mes-1 and Calu-3) with IC50 values ranging from 2.3–6.7 mM. Moreover, CnBu showed much higher selectivity between cancer and normal cells, as suggested by its IC50 value towards BEAS-2B human normal bronchial epithelial cells reaching 22.3 mM. CnBu also significantly inhibited the growth of A549 cells in a dose-dependent manner through anti-migration and anti-invasion.
    [Show full text]
  • The Anticancer Effects of Cinobufagin on Hepatocellular Carcinoma Huh‑7 Cells Are Associated with Activation of the P73 Signaling Pathway
    MOLECULAR MEDICINE REPORTS 19: 4119-4128, 2019 The anticancer effects of cinobufagin on hepatocellular carcinoma Huh‑7 cells are associated with activation of the p73 signaling pathway LEI ZHAO1,2*, LINA FU3*, ZHONGWEI XU1, RONG FAN1, RUICHENG XU1, RONG FU1, SHUANG ZOU1, CONGCONG WANG1, YAN ZHANG1, JIABAO WANG1, JUN BAO1, ZHIMEI WANG1, XIAOJIE HOU1, YUPIAO ZHENG4, ERQING DAI2 and FENGMEI WANG4 1Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309; 2Hepatology Department of Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin 300162; 3Department of Gastroenterology, Tianjin Fourth Central Hospital, Tianjin 300140; 4Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, P.R. China Received July 12, 2018; Accepted February 14, 2019 DOI: 10.3892/mmr.2019.10108 Abstract. The Na+/K+-ATPase inhibitor cinobufagin exhibits as well as the phosphorylation of p53 and mouse double minute numerous anticancer effects on hepatocellular carcinoma (HCC) 2 homolog, were significantly decreased in Huh‑7 cells treated cells expressing wild-type p53 via inhibition of aurora kinase A with 5 µmol/l cinobufagin for 24 h. Conversely, the expression (AURKA) and activation of p53 signaling. However, the effects of levels of Bcl-2-associated X protein, p21, p53 upregulated modu- cinobufagin on HCC cells expressing mutant p53 remain unclear. lator of apoptosis and phorbol-12-myristate-13-acetate-induced In the present study, the anticancer effects of cinobufagin were protein 1, were significantly increased by cinobufagin treat- investigated on HCC Huh-7 cells with mutant p53, and the effects ment. Overexpression or inhibition of AURKA suppressed or of AURKA overexpression or inhibition on the anticancer effects promoted the anticancer effects of cinobufagin on Huh-7 cells, of cinobufagin were analyzed.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0220580 A1 Rubin Et Al
    US 2016O220580A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0220580 A1 Rubin et al. (43) Pub. Date: Aug. 4, 2016 (54) SMALL MOLECULESCREENING FOR (60) Provisional application No. 61/497,708, filed on Jun. MOUSE SATELLITE CELL PROLIFERATION 16, 2011. (71) Applicant: PRESIDENT AND FELLOWS OF Publication Classification HARVARD COLLEGE, Cambridge, (51) Int. Cl. MA (US) A 6LX3/553 (2006.01) (72) Inventors: Lee L. Rubin, Wellesley, MA (US); A613 L/496 (2006.01) Amanda Gee, Alexandria, VA (US); A613 L/4439 (2006.01) Amy J. Wagers, Cambridge, MA (US) A613 L/404 (2006.01) (52) U.S. Cl. CPC ............. A6 IK3I/553 (2013.01); A61 K3I/404 (21) Appl. No.: 15/012,656 (2013.01); A61 K3I/496 (2013.01); A61 K 31/4439 (2013.01) (22) Filed: Feb. 1, 2016 (57) ABSTRACT The invention provides methods for inducing, enhancing or Related U.S. Application Data increasing satellite cell proliferation, and an assay for screen (63) Continuation-in-part of application No. 14/126,716, ing for a candidate compound for inducing, enhancing or filed on Jun. 13, 2014, now Pat. No. 9.248,185, filed as increasing satellite cell proliferation. Also provided are meth application No. PCT/US2012/042964 on Jun. 18, ods for repairing or regenerating a damaged muscle tissue of 2012. a Subject. Patent Application Publication Aug. 4, 2016 Sheet 1 of 44 US 2016/0220580 A1 FIG. A Patent Application Publication Aug. 4, 2016 Sheet 2 of 44 US 2016/0220580 A1 FIG. C. FIG. 2A Patent Application Publication Aug.
    [Show full text]
  • World Journal of Pharmaceutical Research Pradhan Et Al
    World Journal of Pharmaceutical Research Pradhan et al. World Journal of Pharmaceutical SJIF ImpactResearch Factor 6.805 Volume 5, Issue 8, 426-443. Review Article ISSN 2277– 7105 ` BUFO SKIN-SECRETIONS ARE SOURCES OF PHARMACOLOGICALLY AND THERAPEUTICALLY SIGNIFICANT COMPOUNDS Dr. Bishnu Charan Pradhan*1 and Shakti Prasad Pradhan2 1Dept. of Zoology Angul Mahila Mahavidyalaya, Angul, Odisha, India. 759122. 2Dept. of Pharmacy. Utkal University, Vanivihar, Bhubaneswar, Odisha, India. ABSTRACT Article Received on 07 June 2016, Amphibians have been occupying a wide range of habitats since they Revised on 28 June 2016, evolved around 363 million-years-ago. Along with legs and lungs, skin Accepted on 18 July 2016 DOI: 10.20959/wjpr20168-6752 played an important role in survival of amphibians and made it possible for them to exploit diverse ecological conditions. Amphibian skin not only helps in avoiding desiccation but also helps in imposing *Corresponding Author Dr. Bishnu Charan defense against predators as well as pathogens. Amphibian skin Pradhan possesses wide variety of chemical compounds, which have potential Dept. of Zoology Angul significance in pharmacology and therapeutics. Toads especially those Mahila Mahavidyalaya, belonging to genus Bufo, are outstanding source of useful granular- Angul, Odisha, India. 759122. gland secretions. Compounds derived from toad skin-secretions can be used as analgesics, painkillers and as medicine against cardiac- problems, multi-drug resistant bacteria, HIV and Cancer. KEYWORDS: Bufadienolides, pharmacology, Bufo skin-secretions, toxins. INTRODUCTION Amphibians started trolling the landmasses of earth about 363 million-years-ago, with Acanthostega and Ichthyostega probably being the earliest of known amphibians (Evans[20] et al 1998). Fossil records elucidate that ancestors of modern amphibians like Frogs, Toads, Caecilians and Salamanders probably evolved about 200 million years ago during the Triassic period.
    [Show full text]