A constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG) has been known to possess antiproliferative properties. In this study, we investigated the anticancer effects of EGCG in human papillomavirus (HPV)-16 associated cervical cancer cell line, CaSki cells. The growth inhibitory mechanism(s) and regulation of gene expression by EGCG were also evaluated. EGCG showed growth inhibitory effects in CaSki cells in a dose-dependent fashion, with an inhibitory dose (ID)(50) of approximately 35 microM. When CaSki cells were further tested for EGCG-induced apoptosis, apoptotic cells were significantly observed after 24 h at 100 microM EGCG. In contrast, an insignificant induction of apoptotic cells was observed at 35 microM EGCG. However, cell cycles at the G1 phase were arrested at 35 microM EGCG, suggesting that cell cycle arrests might precede apoptosis. When CaSki cells were tested for their gene expression using 384 cDNA microarray, an alteration in the gene expression was observed by EGCG treatment. EGCG downregulated the expression of 16 genes over time more than twofold. In contrast, EGCG upregulated the expression of four genes more than twofold, suggesting a possible gene regulatory role of EGCG. This data supports that EGCG can inhibit cervical cancer cell growth through induction of apoptosis and cell cycle arrest as well as regulation of gene expression in vitro. Furthermore, in vivo antitumor effects of EGCG were also observed. Thus, EGCG likely provides an additional option for a new and potential drug approach for cervical cancer patients.

We studied the estrogenic activity and cellular effect of wild yam extract in MCF-7 human breast cancer cells. The extract increased the activity of the progesterone receptor and pS2 genes at the mRNA levels in human breast cancer MCF-7 cells, although the effects were not as prominent as those of 17beta-estradiol (E(2)). Western blot analysis showed that the level of estrogen receptor alpha protein was down-regulated after treatment with E(2) or wild yam extract. Wild yam extract also inhibited proliferation of MCF-7 cells. These data indicate that wild yam extract acts as a weak phytoestrogen and protects against proliferation in human breast carcinoma MCF-7 cells.

Abstract. As 2 O 3 has been reported to induce apoptosis and inhibit the proliferation of various human cancer cells. We evaluated the ability of a novel arsenic compound, As 4 O 6 , along with As 2 O 3 in vitro and in vivo. To examine the levels of apoptosis of HPV 16-positive SiHa cervical cancer cell, flow cytometry and Western blotting were employed at various time intervals after two arsenic compound treatments. Ingenuity Pathway Analysis (IPA) was applied to investigate the differential cell death pathway of As 4 O 6 and As 2 O 3 . The results showed that As 4 O 6 was more effective in suppressing SiHa cell growth in vitro and in vivo compared to As 2 O 3 . In addition, the cell cycle was arrested at the sub-G 1 phase by As 4 O 6 . Western blot analysis showed that the proliferating cell nuclear antigen (PCNA) and Bcl-X L with sequence homology to Bcl-2 were significantly suppressed by As 4 O 6 . However, the apoptosis-related proteins such as p21 and Bax were overexpressed by As 4 O 6 . IPA suggested that there is a significant difference between As 2 O 3 -and As 4 O 6 -induced cell death pathways. Taken together, As 4 O 6 has a specific cell death pathway and possesses more potent anti-tumor effects on human cervical cancer cells in vitro and in vivo.

BackgroundWe previously reported that the USP17 deubiquitinating enzyme having hyaluronan binding motifs (HABMs) interacts with human SDS3 (suppressor of defective silencing 3) and specifically deubiquitinates Lys-63 branched polyubiquitination of SDS3 resulting in negative regulation of histone deacetylase (HDAC) activity in cancer cells. Furthermore, USP17 and SDS3 mutually interact with each other to block cell proliferation in HeLa cells but the mechanism for this inhibition in cell proliferation is not known. We wished to investigate whether the HABMs of USP17 were responsible for tumor suppression activity.Methodology/Principal FindingsSimilarly to USP17, we have identified that SDS3 also has three consecutive HABMs and shows direct binding with hyaluronan (HA) using cetylpyridinium chloride (CPC) assay. Additionally, HA oligosaccharides (6-18 sugar units) competitively block binding of endogenous HA polymer to HA binding proteins. Thus, administration of HA oligosaccharides antagonizes the interaction between HA and USP17 or SDS3. Interestingly, HABMs deleted USP17 showed lesser interaction with SDS3 but retain its deubiquitinating activity towards SDS3. The deletion of HABMs of USP17 could not alter its functional regulation on SDS3-associated HDAC activity. Furthermore, to explore whether HABMs in USP17 and SDS3 are responsible for the inhibition of cell proliferation, we investigated the effect of USP17 and SDS3-lacking HABMs on cell proliferation by soft agar, apoptosis, cell migration and cell proliferation assays.ConclusionsOur results have demonstrated that these HABMs in USP17 and its substrate SDS3 are mainly involved in the inhibition of anchorage-independent tumor growth.

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Purpose: D iarsenic oxide, As2O 3, has been reported to be effective in treating acute leukemia, and induce apoptosis in many tumor cells. In this study, the ability of a novel arsenical compound, As4O 6 (tetraarsenic oxide), along with As2O 3, for its ability to induce cell growth inhibition, as well as apoptosis, in human cervical cancer cells, S iH a cells, were evaluated in vitro.M aterials and M ethods: To examine the levels of apoptosis, S iH a cells were given two sensitive doses, 0.5 and 1μM , of arsenical compounds, and a D N A fragmentation assay and FAC S analysis were then conducted. In addition, a W estern blotting assay was performed to identify target molecules for apoptosis.R esults: Both As2O 3 and As4O 6 induced dosedependent inhibition of S iH a cell proliferation. In particular, As4O 6 was more effective at suppressing SiHa cell growth than As2O 3. In parallel with the inhibition of cell proliferation, As4O 6 caused a significantly greater increase in the sub-G 1 cell population than As2O 3, as determined by propidium iodide D N A staining. This was confirmed by a D N A fragmentation assay and annexin V staining. The W estern blotting analysis also showed that the expression of proliferating cell nuclear antigen (P C N A) was suppressed to a significantly greater extent by As4O 6 than As2O 3 at a dose of 0.5μM . H owever, the apoptosis-related protein, Bax, was expressed to a significantly greater extent due to As4O 6 than As2O 3.C onclusion: Taken together, these findings suggest that a novel arsenic compound, As4O 6, possesses more potent anti-proliferative effects on human cervical cancer cells, with the induction of apoptosis also, at least via the activation of Bax protein in vitro. (C ancer R es Treat. 2005;37:307-312)

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