ABSTRACT
Nineteen terpenoids, including macrocyclic diterpenes, diterpenic lactones and other polycyclic diterpenes, steroids and a triterpene isolated from the methanolic extracts of Euphorbia species, were evaluated for their potential antineoplastic activity in various human cancer cell lines that were derived from three tumor entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) carcinomas. Furthermore, different multidrug-resistant variants of these cancer cell lines with over-expression of MDR1/P-gp or no MDR1/P-gp expression were also investigated. In parental drug-sensitive cell lines, the tested compounds showed a moderate/weak antiproliferative effect or were inactive. Most of them were found more effective in drug-resistant cells than in the parental, drug-sensitive ones, and some of them showed high antineoplastic efficacy in classical or atypical drug-resistant cells. The most active compounds were the lathyrane diterpenes latilagascenes C and D, and the diterpenic lactones 3beta-acetoxy-helioscopinolide B and helioscopinolide E which exhibited high antineoplastic activities against the drug-resistant subline EPG85-257RDB derived from gastric carcinoma. In addition, the macrocyclic lathyrane diterpene jolkinol B was found to be highly effective in the multidrug-resistant variant HT-29RNOV.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma/drug therapy , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Euphorbia/chemistry , Plant Extracts/therapeutic use , Terpenes/therapeutic use , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Drug Resistance, Multiple/drug effects , Humans , Pancreatic Neoplasms/drug therapy , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Stomach Neoplasms/drug therapy , Terpenes/isolation & purification , Terpenes/pharmacologyABSTRACT
Using the whole-cell patch-clamp technique, the influence of selected multidrug resistance modulators, both plant-derived compounds and derivatives on the activity of voltage-gated potassium channels Kv1.3 was investigated. Twelve compounds with phenolic and terpenic structures were tested: the stilbenes piceatannol (1) and its tetramethoxy (2) and tetracetoxy (3) derivatives, the flavonoids naringenin (4) and its methylated derivatives: naringenin-4',7-dimethylether (5) and naringenin-7-methylether (6), and aromadendrin (7), the coumarins esculetin (8) and scopoletin (9) and ent-abietane diterpenes, helioscopinolide B (10) and its 3beta-acetoxy derivative (11) and helioscopinolide E (12). The studies were performed on a model system with Kv1.3 channels endogenously expressed in human T lymphocytes. Obtained data provide evidence that compounds 2, 5 and 6 applied at 30 microM inhibited the amplitude of recorded currents to 31%, 4% and 29% of its control value, respectively. On the other hand, compounds 3, 4, 7-12 (at 30 microM) and compound 1 (at 40 microM) did not affect significantly the channel activity. These results indicate that some methoxy-derivatives of the tested compounds are effective inhibitors of Kv1.3 channels. Since the inhibition of Kv1.3 channels may inhibit the proliferation of prostate, breast and colon cancer cells expressing these channels, the channel inhibitors may exert an antiproliferative action. This action combined with a simultaneous modulation of the multidrug resistance may be significant for a potential application of these compounds in cancer chemotherapy.
Subject(s)
Kv1.3 Potassium Channel/drug effects , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Phenols/pharmacology , Terpenes/pharmacology , Cell Proliferation/drug effects , Euphorbia/chemistry , Humans , In Vitro Techniques , Kv1.3 Potassium Channel/metabolism , Patch-Clamp Techniques , Phenols/isolation & purification , T-Lymphocytes/metabolism , Terpenes/isolation & purificationABSTRACT
A phytochemical reinvestigation of the whole plant of Euphorbia segetalis yielded five tetracyclic triterpenes: 3beta-hydroxy-cycloart-25-en-24-one (1), cycloart-25-ene-3beta,24-diol (2), cycloart-23-ene-3beta,25-diol (3), lanosta-7,9(11),24-trien-3beta-ol (4) and lanosta-7,9(11),24(31)-trien-3beta-ol (5). beta-acetoxy-cycloart-25-en-24-one (1a) and glutinol (6), lupenone (7), dammaranodienol (9), cycloartenol acetate (10), 24-methylenecycloartanol acetate (11) and beta-sitosterol (12), isolated previously, were evaluated for their antiviral activities against Herpes simplex virus (HSV) and African swine fever virus (ASFV). Lupenone exhibited strong viral plaque inhibitory effect against HSV-1 and HSV-2. The in vitro antifungal and antibacterial activities of la, cycloart-23-ene-3beta,25-diol, 3-acetate (3a) and 6-12 were also investigated.
