[Show abstract][Hide abstract] ABSTRACT: Given that the proteasome is essential for multiple cellular processes by degrading diverse regulatory proteins, inhibition of the proteasome has emerged as an attractive target for anti-cancer therapy. YSY01A is a novel small molecule compound targeting the proteasome. The compound was found to suppress viability of MCF-7 cells and cause limited cell membrane damage as determined by sulforhodamine B assay (SRB) and CytoTox 96(®) non-radioactive cytotoxicity assay. High-content screening (HCS) further shows that YSY01A treatment induces cell cycle arrest on G2 phase within 24 hrs. Label-free quantitative proteomics (LFQP), which allows extensive comparison of cellular responses following YSY01A treatment, suggests that various regulatory proteins including cell cycle associated proteins and PI3K/Akt pathway may be affected. Furthermore, YSY01A increases p-CDC-2, p-FOXO3a, p53, p21(Cip1) and p27(Kip1) but decreases p-Akt, p-ERα as confirmed by Western blotting. Therefore, YSY01A represents a potential therapeutic for breast cancer MCF-7 by inducing G2 phase arrest via ERα and PI3K/Akt pathways.
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis inhibitors combined with chemotherapeutic drugs have significant efficacy in the treatment of a variety of cancers. Pseudolarix acid B (PAB) is a traditional pregnancy-terminating agent, which has previously been shown to reduce tumor growth and angiogenesis. In this study, we used the high content screening assay to examine the effects of PAB on human umbilical vein endothelial cells (HUVECs). Two hepatocarcinoma 22-transplanted mouse models were used to determine PAB efficacy in combination with 5-fluorouracil (5-Fu). Our results suggested that PAB (0.156-1.250 μM) inhibited HUVECs motility in a concentration-dependent manner without obvious cytotoxicity in vitro. In vivo, PAB (25 mg/kg/day) promoted the anti-tumor efficacy of 5-Fu (5 mg/kg/2 days) in combination therapy, resulting in significantly higher tumor inhibition rates, lower microvessel density values, and prolonged survival times. It was also demonstrated that PAB acted by blocking the cell cycle at both the G(1)/S boundary and M phase, down-regulation of vascular endothelial growth factor, hypoxia-inducible factor 1α and cyclin E expression, and up-regulation of cdc2 expression. These observations provide the first evidence that PAB in combination with 5-Fu may be useful in cancer treatment.
Preview · Article · May 2012 · Acta Biochimica et Biophysica Sinica
[Show abstract][Hide abstract] ABSTRACT: CS-1, a new alkaloid with a molecular formula of C(21)H(20)O(8)N(2)S, is extracted from traditional Chinese medicine. Previous studies have shown that CS-1 can inhibit the proliferation of several human carcinoma cells in vivo and in vitro. The aims of this study are to investigate the anti-tumor effect and mechanism of CS-1 in epidermal growth factor receptor (EGFR) signaling pathway in human A431 cell line. Through the sulforhodamine B assay, we found that CS-1 inhibited A431 cell proliferation in the concentration- and time-dependent manners. The inhibitory rate ranged from 14.5% to 87.8% after 24 h of incubation. High content screening (HCS) multi-parameters cytotoxicity analysis showed that CS-1 at high concentration had slight cytotoxicity that resulted from the cell permeabilization and slight reduction in total mitochondrial mass, whereas no change in nucleus size/morphology and lysosomal mass-pH was found. The cytotoxicity of CS-1 was not a major reason for its anti-proliferative effect. Cell cycle analysis indicated that CS-1 induced G1-phase arrest in A431 cells in a time-dependent manner at high concentration (2.5 μM), and S-phase arrest at low concentration (0.625 μM). The HCS assay also showed that CS-1 could inhibit the EGFR internalization, extracellular-signal-regulated kinase (Erk)/mitogen-activated protein kinase translocation to nucleus, the accumulation of phosphorylated protein kinase B (Akt), signal transducer and activator of transcription 3 (STAT3), and cyclin D1 in the nucleus. These results were confirmed by the western blot analysis. CS-1 might inhibit the epidermal growth factor binding to its receptor, resulting in the inhibition of the accumulation of phosphorylated Erk and Akt, and STAT3 in the nucleus, and affecting the transcription of cyclin D1 and cell cycle arrest in G1/S phase.
Preview · Article · Dec 2011 · Acta Biochimica et Biophysica Sinica
[Show abstract][Hide abstract] ABSTRACT: We report, for the first time, the synthesis and biological activities of 8-deaza-5,6,7,8-tetrahydroaminopterin 9, and the 5-substituted and 5,10-disubstituted analogues 11, 13, 15, and 17. The analogues were obtained from key compound diethyl 8-deaza-5,6,7,8-tetrahydroaminopterin 8 following the catalytic reduction of the pyridine ring of diethyl 8-deaza aminopterin 5. The five novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives were assayed in vitro for their cytotoxicity on BGC-823, HL-60, Bel-7402 and Hela tumor cell lines, and inhibition on recombinant human dihydrofolate reductase (DHFR), among which the most potent molecule (compound 9) was about 4- to 10-fold poorer than MTX on the four kinds of tumor cell lines, and its effect on DHFR was about 17-fold poorer than MTX. The docking studies were followed to explain the biological testing results.
No preview · Article · Jun 2008 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: A series of novel 2-oxocycloalkylsulfonamides (4) were synthesized and their structures confirmed by IR, (1)H NMR, and elemental analysis. The bioassay showed that they have fair to excellent fungicidal activities against Botrytis cinerea Pers and Sclerotinia sclerotiorum. Among them, compounds 4A(10), 4A(11), 4A(12), 4B(2), and 4B(3), the EC(50) values of which were 2.12, 3.66, 3.96, 2.38, and 2.43 microg/mL, respectively, displayed excellent fungicidal activity against B. cinerea Pers, and are comparable with commercial fungicide procymidone (the EC(50) value is 2.45 microg/mL). 3D QSAR against B. cinerea Pers was studied, a statistically significant and chemically meaningful CoMFA model was developed and some compounds which have a high predicted activity were forecasted. In addition, the bioassay also showed that the compounds have good inhibitory activities against human tumor cells HL-60, BGC-823, Bel-7402 and KB. It is interesting to point out that the antitumor activities of compounds 4 are in accordance with their fungicidal activity to a great extent: compounds having relatively best antitumor activities (4A(10), 4A(11), 4A(12), and 4B(3)) also displayed excellent fungicidal activity.
No preview · Article · May 2008 · Bioorganic & medicinal chemistry