Identification of chrysoplenetin from Vitex negundo as a potential cytotoxic agent against PANC-1 and a panel of 39 human cancer cell lines (JFCR-39).

Human pancreatic cancer is known to be the most deadly disease with the lowest 5-year survival rate and is resistant to well known conventional chemotherapeutic drugs in clinical use. Screening of medicinal plants from Myanmar utilizing antiausterity strategy led to the identification of Vitex negundo as one of the medicinal plants having potent preferential cytotoxic activity against PANC-1 human pancreatic cancer cells. Bioactivity-guided phytochemical investigation led to the isolation of chrysoplenetin (1) and chrysosplenol D (2) as the active constituents with a PC(50) value of 3.4 µg/mL and 4.6 µg/mL, respectively, against PANC-1 cells. Both these compounds induced apoptosis-like morphological changes in PANC-1 cells. Chrysoplenetin was further tested against a panel of 39 human cancer cell lines (JFCR-39) at the Japanese Foundation for Cancer Research, and 25 cell lines belonging to lung, breast, CNS, colon, melanoma, ovarian, prostate cancer and stomach cancer cell lines were found to be highly sensitive to chrysoplenetin at a submicromolar range. In the JFCR-39 panel, lung NCI-H522, ovarian OVCAR-3 and prostate PC-3 cells were found to be most sensitive with GI(50) of 0.12, 0.18 and 0.17 µm, respectively. The COMPARE analysis suggested that the molecular mode of action of chrysoplenetin was unique compared with the existing anticancer drugs.

Triterpene glycosides from Curculigo orchioides and their cytotoxic activity.

Six new cycloartane glycosides (1-6) were isolated from the rhizomes of Curculigo orchioides. The structures of 1-6 were determined by spectroscopic analyses and the results of hydrolytic cleavage. Compounds 1-6, and their common aglycone (1a), were evaluated for cytotoxic activity against HL-60 human leukemia cells. Compounds 1 and 1a showed cytotoxic activity against HL-60 cells with IC(50) values of 9.0 and 1.8 microM, respectively. The cancer cell growth inhibition of 1a was also examined using a panel of 39 human cancer cell lines in the Japanese Foundation for Cancer Research.

Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor.

Angiogenesis is known to be required for tumour growth and metastasis. Recent reports indicated that phosphatidylinositol 3-kinase (PI3K) promoted angiogenesis by inducing expressions of HIF-1alpha and vascular endothelial growth factor (VEGF). The present study aims to investigate the antiangiogenic effect of ZSTK474, a novel pan-PI3K inhibitor. ZSTK474 significantly inhibited tumour growth in the RXF-631L xenograft model. Immunohistochemical staining of the tumour tissue with anti-von Willebrand Factor antibody showed a significantly reduced number of microvessels in the ZSTK474-treated mice, suggesting the highly promising antiangiogenic activity in vivo. In human umbilical vein endothelial cells (HUVECs), submicromolar concentrations of ZSTK474 inhibited cell growth, blocked VEGF-induced cell migration and the tube formation, and thus revealed potent in vitro antiangiogenic activity. Furthermore, ZSTK474 inhibited phosphorylation of Akt at submicromolar concentrations. In RXF-631L cancer cells, on the other hand, ZSTK474 treatment inhibited the expression of HIF-1alpha and secretion of VEGF. Together, these results suggest that ZSTK474 has potent antiangiogenic activity, which could be attributed to dual-target inhibitory properties: inhibition of VEGF secretion by cancer cells and inhibition of PI3K in endothelial cells.

Evaluation of action mechanisms of toxic chemicals using JFCR39, a panel of human cancer cell lines.

We previously established a panel of human cancer cell lines, JFCR39, coupled to an anticancer drug activity database; this panel is comparable with the NCI60 panel developed by the National Cancer Institute. The JFCR39 system can be used to predict the molecular targets or evaluate the action mechanisms of the test compounds by comparing their cell growth inhibition profiles (i.e., fingerprints) with those of the standard anticancer drugs using the COMPARE program. In this study, we used this drug activity database-coupled JFCR39 system to evaluate the action mechanisms of various chemical compounds, including toxic chemicals, agricultural chemicals, drugs, and synthetic intermediates. Fingerprints of 130 chemicals were determined and stored in the database. Sixty-nine of 130 chemicals ( approximately 60%) satisfied our criteria for the further analysis and were classified by cluster analysis of the fingerprints of these chemicals and several standard anticancer drugs into the following three clusters: 1) anticancer drugs, 2) chemicals that shared similar action mechanisms (for example, ouabain and digoxin), and 3) chemicals whose action mechanisms were unknown. These results suggested that chemicals belonging to a cluster (i.e., a cluster of toxic chemicals, a cluster of anticancer drugs, etc.) shared similar action mechanism. In summary, the JFCR39 system can classify chemicals based on their fingerprints, even when their action mechanisms are unknown, and it is highly probable that the chemicals within a cluster share common action mechanisms.

Sesquiterpenoids and flavonoids from the aerial parts of Tithonia diversifolia and their cytotoxic activity.

Cytotoxicity-guided fractionation of the 80% EtOH extract of Tithonia diversifolia has resulted in the isolation of twelve sesquiterpenoids (1-12), including three new ones (4, 10, 12), and three known flavonoids (13-15). The structures of the new compounds were determined by analysis of their spectroscopic data. The isolated compounds showed cytotoxic activity against HL-60 leukemia cells with IC(50) values ranging from 0.13 to 13.0 microM, when etoposide used as a positive control gave an IC(50) value of 0.43 microM. The cancer growth inhibitory property of 9, the main cytotoxic compound in T. diversifolia, was examined using a disease-oriented panel composed of 39 human cancer cell lines in the Japanese Foundation for Cancer Research.

Potent antitumor activity of 3,4-seco-8betaH-Ferna-4(23),9(11)-dien-3-oic acid (EC-2) and 3,4-seco-Oleana-4(23),18-dien-3-oic acid (EC-4), evaluated by an in vitro human cancer cell line panel.

3,4-seco-8beta H-Ferna-4(23),9(11)-dien-3-oic acid (EC-2) (1) and 3,4-seco-oleana-4(23),18-dien-3-oic acid (EC-4) (2) isolated from the whole herb of Euphorbia chamaesyce L. were evaluated for their anti-tumor activities using a panel including 39 human cancer cell lines (HCC) coupled with a drug sensitivity database. Compounds 1 and 2 showed strong cytotoxicity against the HCC panel, even though alcohols 1A and 2A and methyl esters 1B and 2B were inactive.

Triterpene saponins from the roots of Clematis chinensis.

A saponin-enriched fraction prepared from the MeOH extract of the roots of Clematis chinensis showed cytotoxic activity against HL-60 promyelocytic leukemia cells, from which five new triterpene saponins based on oleanolic acid, along with three known saponins, were isolated. The structures of the new saponins were determined on the basis of spectroscopic analysis, including extensive 1D and 2D NMR data and hydrolysis followed by chromatographic and spectroscopic analysis. Among the isolated saponins, monodesmosidic saponins exhibited cytotoxic activities against cultured tumor cells.

New cytotoxic oleanane-type triterpenoids from the cones of Liquidamber styraciflua.

Two new oleanane-type triterpenoids (1 and 2), together with two known compounds, 6beta-hydroxy-3-oxo-lup-20(29)-en-28-oic acid (3) and 3,11-dioxoolean-12-en-28-oic acid (4), were isolated from the stem bark of Liquidamber styraciflua. The structures of 1 and 2 were determined to be 25-acetoxy-3alpha-hydroxyolean-12-en-28-oic acid (1) and 3alpha,25-dihydroxyolean-12-en-28-oic acid (2) on the basis of spectroscopic methods and chemical conversion. Compound 1 showed strong cytotoxicity against a disease-oriented panel of 39 human cancer cell lines, although compounds 2, 3, and 4 showed weaker activity compared to 1.

[Chemical evaluation by cancer cell line panel and its role in molecular target-based anticancer drug screening].

Mechanism-based or target-based evaluation of chemicals is important in the discovery and development of anticancer drugs. A new scale for the mechanism-oriented evaluation is acquired by creating a database of drugs that includes their activities concerning growth inhibition against a set of cancer cell lines and by employing a specific data-mining method (Paull KD, et al: J Natl Cancer Inst 81: 1088-1092, 1989). According to this principle, we have established a new system for drug evaluation using a panel of 39 human cancer cell lines, JFCR-39 Cell Line Panel. The JFCR-39 Cell Line Panel is a system combining a wet system (drug-sensitivity test) and a dry system (data base and its mining), and can predict the mechanism of action of chemicals. Therefore, it is useful in anticancer drug discovery. The JFCR-39 Cell Line Panel now plays an important role as a core drug evaluation system in the molecular target-based drug screening conducted by Screening Committee of New Anticancer Agents supported by Grant-in-Aid for Scientific Research on Priority Area "Cancer" from The Ministry of Education, Culture, Sports, Science and Technology, Japan. I outlined the JFCR-39 Cell Line Panel in this review.

Production of biologically active taxoids by a callus culture of Taxus cuspidata.

Ten known taxoids, paclitaxel, 7-epi-taxol, taxol C, baccatin VI, taxayuntin C, taxuyunnanine C and its analogues (2-5), and yunnanxane (6), and an abietane, taxamairin A, were produced in the callus culture of Taxus cuspidata cultivated on a modified Gamborg's B5 medium in the presence of 0.5 mg/L NAA. After stimulation with 100 microM methyl jasmonate, five more taxoids, cephalomannine, 1beta-dehydroxybaccatin VI, taxinine NN-11 (1), baccatin I, and 2alpha-acetoxytaxusin, and one more abietane, taxamairin C, were found in addition to the above-mentioned compounds. It was also observed that the content of the products increased over three times. Taxinine NN-11 (1) is a new taxane whose structure was assigned as 5alpha,13alpha-diacetoxy-9alpha-cinnamoyloxy-4(20),11-taxadien-10beta-ol by analysis of its spectral data. Taxinine NN-11 (1) exhibited significant MDR reversal activity toward 2780 AD tumor cells. The results of primary screening based on 39 human cancer cell lines suggest that 1 also belongs to a new mechanistic class. Efficient production of 1 was investigated using the callus culture of T. cuspidata.