glaucarubin and Neoplasms

The search for new anti-cancer drugs is one of the most prominent research areas of natural products. Numerous active compounds isolated from Brazilian Cerrado plant species have been studied with promising results.. To investigate the cytotoxic potential of 412 extracts from Brazilian Cerrado plants used in traditional medicine belonging to 21 families against tumor cell lines in culture.. Maceration of 50 plant species resulted in 412 hexane, dichloromethane, ethanol and hydroalcohol extracts. The cytotoxicity of the extracts was tested against human colon carcinoma (HCT-8), melanoma (MDA-MB-435), and brain (SF-295) tumor cell lines, using the thiazolyl blue test (MTT) assay. Bioassay-guided fractionation was performed for one active extract.. Twenty-eight of the 412 tested extracts demonstrated a substantial antiproliferative effect, at least 85% inhibition of cell proliferation at 50 microg/mL against one or more cell lines. Those extracts are obtained from different parts of Anacardiaceae, Annonaceae, Apocynaceae, Clusiaceae, Flacourtiaceae, Sapindaceae, Sapotaceae, Simaroubaceae and Zingiberaceae. Complete dose-response curves were generated and IC(50) values were calculated for these active extracts against four cell lines HCT-8, MDA-MB-435, SF-295 and HL-60 (leukemia), and their direct cytotoxic effects were determined. In summary, 14 extracts of 13 species showed toxicity in all tested tumor cell lines, with IC(50) values ranging from 0.1 to 19.1 microg/mL. The strongest cytotoxic activity was found for the hexane extract of Casearia sylvestris var. lingua stem bark, with an IC(50) of 0.1 microg/mL for HCT-8, 0.9 microg/mL for SF-295, 1.2 microg/mL for MDA-MB-435, and 1.3 microg/mL for HL-60, and Simarouba versicolor root bark, with an IC(50) of 0.5 microg/mL for HCT-8, 0.7 microg/mL for SF-295, 1.5 microg/mL for MDA-MB-435, 1.1 microg/mL for HL-60. Bioassay-guided fractionation of the last extract led to the isolation of glaucarubinone, which showed pronounced activity against the four cell lines studied. Further studies of the active extracts are necessary for chemical characterization of the active compounds and more extensive biological evaluations.

Topics: Antineoplastic Agents, Phytogenic; Brazil; Casearia; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ecosystem; Glaucarubin; Humans; Inhibitory Concentration 50; Magnoliopsida; Medicine, Traditional; Neoplasms; Phytotherapy; Plant Extracts; Plant Structures; Plants, Medicinal; Simarouba

A series of glaucarubinone analogues, obtained from natural sources as well as synthesized by us, were studied both in vitro and in vivo. The focus of the in vitro assessment was to define solid tumor-selective compounds by quantitating differential cytotoxic activity between murine and human solid tumor cells and either murine leukemia or normal cells. Subsequent in vivo studies were aimed at determining the therapeutic efficacy of these analogues against the murine models. Structure-activity analysis consequent to both the in vitro and in vivo studies demonstrated that few changes could be made in the parent glaucarubinone structure (outside of the C-15 position) without abrogating either cytotoxicity or potency. However, significant changes could be made at the C-15 position which modified, either enhanced or diminished, in vitro differential cytotoxicity, potency, human solid tumor selectively, and differential cytotoxicity to a MDR-expressing murine mammary tumor.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Glaucarubin; Humans; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasms; Structure-Activity Relationship

Bruceoside C [5], a new quassinoid glucoside, and related compounds were isolated from Brucea javanica, and their structures were elucidated by spectral data. Bruceoside C showed potent cytotoxicities against KB, A-549, RPMI, and TE-671 tumor cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; Glaucarubin; Humans; Magnetic Resonance Spectroscopy; Neoplasms; Plants, Medicinal; Quassins; Tumor Cells, Cultured

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

Topics: Antineoplastic Agents, Phytogenic; Drug Evaluation; Glaucarubin; Half-Life; Humans; Hypotension; Infusions, Parenteral; Liver; Neoplasms; Phenanthrenes; Quassins; Radioimmunoassay