ABSTRACT
Brazilein, a bioactive compound isolated from Caesalpinia sappan L., has long been used in oriental folk medicines. Cancer metastasis is a primary cause of cancer death. However, the anti-metastatic effects of brazilein remain elusive. In this study, we found that brazilein inhibited human breast cancer MDA-MB-231 cell migration and invasion using wound-healing assay and Boyden chamber assay. The results of Western blot, gelatin zymography and reversed transcription-PCR analysis showed that brazilein suppressed matrix metalloproteinase-2 (MMP-2) expression in a concentration-dependent manner. Brazilein also decreased the nuclear protein level of nuclear factor kappaB (NF-κB). Brazilein potently suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), phosphatidylinositide-3-kinase (PI3K) and Akt, but did not affect phosphorylation of extracellular signal regulating kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK). Additionally, treatment of SB203580 (p38 MAPK inhibitor) or wortmannin (PI3K inhibitor) resulted in a reduced activity and expression of MMP-2 as well as inhibition on cell migration and invasion in MDA-MB-231 cells. Taken together, these results suggest that brazilein inhibition of MDA-MB-231 cells may be mediated through inactivation of both PI3K/Akt and p38 MAPK signaling pathways, leading to inhibitory effect on NF-κB activation. Consequently, brazilein suppresses MMP-2 expression, and thus confers anti-migration and anti-invasion of MDA-MB-231 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Breast Neoplasms/drug therapy , Indenes/pharmacology , Matrix Metalloproteinase Inhibitors/pharmacology , Blotting, Western , Cell Line, Tumor , Cell Movement/drug effects , Female , Humans , Molecular Structure , NF-kappa B/chemistry , NF-kappa B/metabolism , Polymerase Chain ReactionABSTRACT
The first total synthesis of the naturally occurring tetracyclic homoisoflavonoid brazilein (1) and 14 new analogs (1a-n) is reported. Target compounds and intermediates were assayed for anti-inflammatory effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB, and for cytotoxic activity against nasopharyngeal (KB), vincristine-resistant nasopharyngeal (KBvin), lung (A549) and prostate (DU-145) human cancer cell lines. The most active compound 1b showed potent effects on superoxide anion generation and elastase release with IC(50) values of 1.2 and 1.9 microM, respectively, and was 65 times more potent than phenylmethylsulfonyl fluoride (PMSF), the positive control, in the latter assay. Additionally, 1b exhibited broad spectrum in vitro anticancer activity with IC(50) values of 6-11 microM against the four tested cancer cell lines.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzopyrans , Cytotoxins/chemical synthesis , Indenes , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cytotoxins/isolation & purification , Cytotoxins/pharmacology , Drug Evaluation, Preclinical/methods , Drugs, Chinese Herbal/chemical synthesis , Drugs, Chinese Herbal/isolation & purification , Drugs, Chinese Herbal/pharmacology , Humans , Neutrophils/drug effects , Neutrophils/immunologyABSTRACT
In a continuing study to isolate novel antitumor agents from rainforest plants, three new isopropenylfurano-beta-naphthoquinones, designated lantalucratins A (1), B (2), and C (3), and three new isoprenyl-alpha-naphthoquinones, designated lantalucratins D (4), E (5), and F (6), were isolated from Lantana involucrata. Their structures were determined on the basis of NMR and X-ray crystallographic analyses. Compounds 1 and 2 showed cytotoxic activities against various human tumor cell lines, including drug-resistant variants, with IC50 values of 1.0-4.9 microM.
Subject(s)
Antineoplastic Agents, Phytogenic/isolation & purification , Lantana/chemistry , Naphthoquinones/isolation & purification , Plants, Medicinal/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Puerto Rico , Tumor Cells, CulturedABSTRACT
Fractionation of the chloroform extract from the aerial part of Argemone mexicana led to the isolation of two benzophenanthridine-type alkaloids, N-demethyloxysanguinarine and pancorine; three benzylisoquinoline-type alkaloids, (+)-1,2,3,4-tetrahydro-1-(2-hydroxymethyl-3,4-dimethoxyphenylmethyl)-6,7-methylenedioxyisoquinoline, (+)-higenamine and (+)-reticuline. Among them, N-demethyloxysanguinarine is a new compound, and (+)-1,2,3,4-tetrahydro-1-(2-hydroxymethyl-3,4-dimethoxyphenylmethyl)-6,7-methylenedioxy-isoquinoline was isolated form a natural source for the first time, to which was assigned a trivial name, (+)-argenaxine. In addition, six known non-alkaloidal compounds were also isolated and identified. All compounds were characterized on the basis of their spectral data and chemical evidences. Some isolated alkaloids from this species were evaluated for their cytotoxicity to human nasopharyngeal carcinoma (HONE-1) and human gastric cancer (NUGC) cell lines. Chelerythrine was found to exhibit significant activity against NUGC cell line, while angoline inhibited both types. (+)-Argenaxine showed moderate activity against the NUGC cell line.
Subject(s)
Alkaloids/toxicity , Argemone/chemistry , Cell Survival/drug effects , Isoquinolines/toxicity , Phenanthridines/isolation & purification , Phenanthridines/toxicity , Plant Components, Aerial/chemistry , Alkaloids/chemistry , Alkaloids/isolation & purification , Humans , Isoquinolines/chemistry , Isoquinolines/isolation & purification , Models, Molecular , Molecular Structure , Nasopharyngeal Neoplasms , Phenanthridines/chemistry , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/toxicity , Stomach Neoplasms , Tumor Cells, CulturedABSTRACT
Two new protopine-type alkaloids, argemexicaine A (1) and argemexicaine B (2), along with thirteen known alkaloids, were isolated from MeOH extracts of Formosan Argemone mexicana L. (Papaveraceae). Physical and spectral analyses, particularly IR and thermo-modulated 1D and 2D NMR, were used to determine the transannular conformations of the isolated protopine-type alkaloids. The known benzo[ c]phenanthridine (+/-)-6-acetonyldihydrochelerythrine (5) exhibited significant anti-HIV activity in H9 lymphocytes with EC50 and TI (Therapeutic Index) values of 1.77 microg/mL and 14.6, respectively.