ABSTRACT
Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The inâ vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10â mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.
Subject(s)
Antineoplastic Agents , Bufanolides , Animals , Mice , Humans , Cell Line, Tumor , Cardiotoxicity/drug therapy , Mice, Nude , Antineoplastic Agents/pharmacology , Bufanolides/chemistry , Apoptosis , Drug Screening Assays, Antitumor , Cell ProliferationABSTRACT
The association between selenium and peptide in gastric cancer is an important research topic. The present study reported the facile synthesis of anticancer bioactive peptide (ACBP)functionalized selenium (ACBPSSe) particles with enhanced anticancer activities and a detailed mechanistic evaluation of their ability to regulate oxidative stress in vitro. Structural and chemical characterizations were revealed by ultraviolet absorption, Fourier transform infrared, Xray photoelectron, nuclear magnetic resonance carbon and hydrogen, energy dispersive Xray spectroscopy and inductively coupled plasma mass spectrometry, as well as scanning electron microscopy. Sulfhydrylation modifications of ACBP were achieved with Sacetylmercaptosuccinic anhydride via chemical absorption. After the polypeptide was modified by sulfhydrylation, the ACBP chain was linked to sulfhydryl groups by amide bonds to form the ACBPchelated selenium complex. Two gastric cancer cell lines (MKN45 and MKN74 cells) demonstrated high susceptibility to ACBPSSe particles and displayed significantly decreased proliferation ability following treatment. The results suggested that the bioactive peptidechelated selenium particles effectively inhibited the proliferation of MKN45 and MKN74 cells in vitro. The genes encoding CDK inhibitor 1A (CDKN1A), cyclin B1, thioredoxin (TXN) and mitogenactivated protein kinase kinase kinase 5 are associated with regulation of oxidative stress, while CDKN1A and TXN protect cells by decreasing oxidative stress and promoting cell growth arrest. Therefore, ACBPSSe may be an ideal chemotherapeutic candidate for human cancer, especially gastric cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Oxidative Stress/drug effects , Peptides/pharmacology , Selenium/pharmacology , Stomach Neoplasms/genetics , Antineoplastic Agents/chemistry , Cell Line , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cyclin B1/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Gene Ontology , Gene Regulatory Networks , Humans , MAP Kinase Kinase Kinase 5/genetics , Peptides/chemistry , Selenium/chemistry , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Thioredoxins/geneticsABSTRACT
Norcantharidin (NCTD) is a demethylated derivative of cantharidin, which is an anticancer active ingredient of traditional Chinese medicine, and is currently used clinically as a routine anti-cancer drug in China. Clarifying the anticancer effect and molecular mechanism of NCTD is critical for its clinical application. Here, we summarized the physiological, chemical, pharmacokinetic characteristics and clinical applications of NCTD. Besides, we mainly focus on its potential multi-target anticancer activities and underlying mechanisms, and discuss the problems existing in clinical application and scientific research of NCTD, so as to provide a potential anticancer therapeutic agent for human malignant tumors.
ABSTRACT
The present study was designed to evaluate the effect of SB injection, which is composed of extracts from the roots of Pulsatilla koreana, Panax ginseng, and Glycyrrhiza glabra, on the viability of canine osteosarcoma and melanoma cells and nonneoplastic canine cells. Cells were treated with SB injection, conventional chemotherapeutic drugs, or a combination of both at various concentrations. Cellular viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry was used to evaluate the cell cycle and apoptosis. SB injection inhibited the growth of osteosarcoma and melanoma cells in a dose-dependent manner. The cell cycle of the affected cells was arrested in the G2/M phase, indicating an anti-proliferative effect. SB injection dose-dependently increased the rate of apoptosis. Furthermore, we found that combining SB injection with chemotherapeutic drugs resulted in a greater reduction in canine malignant cell proliferation than either treatment alone. SB injection did not affect the viability of peripheral blood mononuclear cells regardless of concentration, which suggested that SB injection did not suppress the activity of normal cells. This study suggested that SB injection can be considered an effective alternative medication for animal cancers in veterinary medicine.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/therapeutic use , Injections , Melanoma/drug therapy , Osteosarcoma/drug therapy , Animals , Annexin A5/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/pharmacology , Cisplatin/therapeutic use , Dogs , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Melanoma/pathology , Osteosarcoma/pathology , PhytotherapyABSTRACT
A series of C4'-substituted oleandrin analogues were designed, synthesized and evaluated for their cytotoxicity towards human cervical carcinoma cell line (HeLa). The structure-activity relationships (SARs) of these compounds were summarized in this paper, and 4'-α-amino-4'-dehydroxyloleandrin 4a (IC50=21.7nM) and 4'-ß-amino-4'-dehydroxyloleandrin 4b (IC50=10.9nM) exhibited stronger cytotoxicity compared with oleandrin (IC50=33.3nM). Furthermore, the cytotoxicity of these two compounds towards another five human cancer cell lines (NCI-H266, A549, Jurkat, HL-60 and PC-3) was also evaluated and the IC50 values of ß-amino derivative 4b were approximately 2-3 folds lower than that of oleandrin.
Subject(s)
Antineoplastic Agents/chemistry , Cardenolides/chemistry , Antineoplastic Agents/chemical synthesis , Cardenolides/chemical synthesis , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , HeLa Cells/drug effects , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Six new cardenolides (1, 2 and 11-14), along with ten known ones, were isolated from the root bark of Calotropis gigantea. The structural determination was accomplished by the 1D- and 2D-NMR spectrum as well as ESIMS analysis. The isolated compounds were evaluated for their in vitro growth inhibitory activity against human A549 and Hela cell lines. The results suggested that some of these cardenolides (compounds 1, 6, and 8) displayed potent cytotoxicities.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Calotropis/chemistry , Cardenolides/pharmacology , Plant Bark/chemistry , Plant Extracts/pharmacology , Plant Roots/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cardenolides/chemistry , Cardenolides/isolation & purification , Cell Survival/drug effects , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/isolation & purificationABSTRACT
Probimane was first synthesized and developed in Shanghai Institute of Materia Medica, Chinese Academy of Science as a novel antit umor agent. Male mice were injected iv 〔14C〕 probimane 3.7?105Bq/20g( 5.62? 107Bq/g ) . At 0.5h,higher radioactivities were found in S87 tumor, kidney, bladder, and vertebra, moderate in skim, lung, liver, blood vessel and gut. The radioactivities tended to decre-aseafter 3h except in the tumor, kidney, and gut in which radioactivities persisted. After 12h, only a trace of radioactivity was detected n intestine. The distribution of probimane correlated with its therepeutic efficacy and toxicity.