It is well-known that proliferation, angiogenesis, and malignant progression oflung cancer are correlated with the overexpression of COX-2 protein. It is already known that NF-κB transcription factor plays an important role inthe modulation of COX-2 expression. To examine whether SAC could block the malignant progression ofhuman NSCLC A-549 cells, we investigated the effects of SAC on the levels of COX-2 positively stained cells. Our results showed that SAC could significantly reduce levels of COX-2 positively stained cells in tumor-bearing mice (Figure 6B). In this study, we also demonstrated that the PI3K/Akt and NF-κB signaling pathways played important roles inthe regulation of cellular proliferation. Furthermore, our results showed that SAC could effectively inhibit the activation of Akt/mTOR signaling pathways. SAC could also significantly inhibit the nuclear activa- tion of NF- κB molecules. Take together, these results indicated that SAC could effectively inhibit the proliferation and malignancy of lung cancer in tumor-bearing mice.
tion, induces apoptosis and has antitumour activity in many human cancer cell lines, including non-smallcelllung cancer cells (Kawamori et al., 1999; Rao et al., 1995;
Verma et al., 1997). Curcumin also exhibits anticancer activities in vitro and in vivo in leukemia WEHI-3 cells (Gajate et al., 2003; Su et al., 2008) and has been shown to act by regulating a variety of antitumour signalling pathways (Kuttan et al., 2007; Lin, 2007). It has been suggested that curcumin acts as an oral cancer preventa- tive agent (Sharma et al., 2004) although few in vivo studies have yet been reported. The present study focused on the anticancer effect of curcumin in vivo in mice, using ahumanlung cancer xenograftmodelof NCI-H460 cells.
Chu,Q., Lee,D.T., Tsao,S.W., Wang,X., and Wong,Y.C. (2007) S-allylcysteine, a water-soluble garlic derivative, suppresses thegrowthofahuman androgen-independent prostate cancer xenograft, CWR22R, under in vivo conditions. BJU Int 99: 925-932.
Chuah,S.C., Moore,P.K., and Zhu,Y.Z. (2007) S-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. Am J Physiol Heart Circ Physiol 293: H2693-H2701.
APOPTOSIS; ANTITUMOR; PRODUCTS; AGENT
Abstract: Curcumin can decrease viable cells through the induction of apoptosis inhumanlung cancer NCI-H460 cells in vitro. However, there are no reports that curcumin can inhibit cancer cells in vivo. In this study, NCI-H460 lung tumour cells were implanted directly into nude mice and divided randomly into four groups to be treated with vehicle, curcumin (30 mg/kg of body weight), curcumin (45 mg/kg of body weight) and doxorubicin (8 mg/kg of body weight). Each agent was injected once ever), 4 days intraperitoneally (i.p.), with treatment starting 4 weeks after inoculation with the NCI-H460 cells. Treatment with 30 mg/kg an 45 mg/kg of curcumin or with 8 mg/kg of doxorubicin resulted ina reduction in tumour incidence, size and weight compared with the control group. The findings indicate that curcumin can inhibit tumour growthina NCI-H460 xenograft animal modelin vivo. Copyright (C) 2010 John Wiley & Sons, Ltd.
results further demonstrated that consumptionof lycopene could increase cleaved caspase-3 levels and augment apoptotic cascades in tumor tissues.
The results not only demonstrated the chemopreventive eﬀects of lycopene in preclinical studies but also suggested a potential application in cancer prevention. Therefore, supple- mentation of lycopene could probably inhibit tumor growth and progression in tumor-bearing mice. To identify the additional roles of lycopene in cancer prevention, we further examined their inhibitory eﬀects on the progression of colorectal tumor. The results demonstrated that lycopene signiﬁcantly inhibit the expression of β-catenin, E-cadherin, COX-2, and phosphoryla- tion ERK1/2 proteins in tumor tissues. Recent studies also reported that increased phosphorylation of ERK1/2 proteins was strongly correlated with the induction of COX-2 and suppression of E-cadherin adherent complex during tumor progression in several types of cancer. 8,10 β-Catenin has come onto the scene and reached central status as an important regulator of several important oncogenes including cyclin D1 and c-Myc during tumor development. Increasing evidence implicates that β-catenin is an important biomarker of malignant colon cancer. Thus, suppression of β-catenin proteins would hinder the progression of colorectal tumor.
important role inthe regulation of cyclinD1, c-Myc and MMP-7 expression.
Moreover, the expression of c-Myc and MMP-7 is strongly correlated with tumor progression of CRC. Therefore, we investigated whether lycopene and fish oil would synergistically suppress the expression ofthe -catenin and c- Myc proteins in vivo. As shown in Fig. 3A, lycopene and fish oil significantly inhibited the expression of -catenin. Furthermore, lycopene and fish oil synergistically suppressed the expression of c-Myc protein in vivo. To examine the chemopreventive effects of lycopene and fish oil, we further identified the distribution of -catenin proteins by using immunohistochemical staining analysis in these tumor-bearing mice. As shown in Fig. 3B, -catenin proteins (brown areas indicated with red arrows) were accumulated inthe nuclei of tumor control group. However, consumptionof lycopene and fish oil significantly blocked nuclear translocalization and reduced nuclear levels of -
Abstract: Our primary studies showed that berberine induced apoptosis inhuman tongue cancer SCC-4 cells in vitro. But there is no report to show berberine inhibited SCC-4 cancer cells in vivo on a murine xenograft animal model. SCC-4 tumor cells were implanted into mice and groups of mice were treated with vehicle, berberine (10 mg/kg of body weight) and doxorubicin (4 mg/kg of body weight). The tested agents were injected once per four days intraperitoneally (i.p.), with treatment starting 4 weeks prior to cells inoculation. Treatment with 4 mg/kg of doxorubicin or with 10 mg/kg of berberine resulted ina reduction in tumor
for 5 min. Total proteins were separated using SDS-PAGE before being transferred to
PVDF membranes, blocked with 5% (v/v) nonfat dry milk in PBS-Tween 20 and
probed with the desired antibody (pAkt, Akt, PI3K, p53, p21, Bax, Bcl-2, caspase-3,
caspase-9, cleaved PARP and cytochrome c) (dilution ratio = 1:1000) overnight at
Tumor volume was less inthe rutin treated mice com- pared with controls. Furthermore, the results showed that tumors that received rutin treatment grew slowly, suggest- ing that complete regression of HL-60 cells xenografts was not achieved using a single treatment. Therefore, this study provided the ﬁrst in vivo evidence for the efﬁcacy ofthe ﬂa- vonoid, rutin, on human leukemia HL-60 cells inxenograft mice. Vinblastine treatment also reduced both tumor weight and volume at a concentration of 1000 times lower than rutin. Multiple rutin treatment may be necessary to achieve complete tumor regression. In conclusion, rutin adminis- tered once i.p. per 4 days at 120 mg/kg was effective in reducing thegrowthofhuman leukemia HL-60 tumors inaxenograftmousemodel. These ﬁndings are the ﬁrst to study examine effects of rutin as a leukemia preventive agent using a leukemia murine xenograftmodel.
Abstract: There are many major causes of cancer death, including metastasis of cancer.
Dihydroaustrasulfone alcoholDihydroaustrasulfone alcohol, which is isolated from marine coral, has shown antioxidant activity, but has not been reported to have an anti-cancer effect. We first discovered that Dihydroaustrasulfone alcohol provided a concentration- dependent inhibitory effect on the migration and motility ofhumannon-smallcelllungcarcinoma (NSCLC) A549 cells by trans-well and wound healing assays. The results ofa zymography assay and Western blot showed that Dihydroaustrasulfone alcohol suppressed 1 2
題名: Targeting ECM/Integrin Interaction with Liposome-Encapsulated Small Interfering RNAs InhibitstheGrowthofHuman Prostate Cancer in Bone inaXenograft Imaging Model. Molecular Therapy
作者: Kristen Bisanz;Magnus Edlund;Bill Spohn;Mien-Chie Hung;Leland W. K. Chung 關鍵詞: small interfering RNA;prostate cancer bone metastasis;integrins, extracellular
ethanol for more than 10 months at room temperature. During the process, most ofthe orangosulfur compounds are changed naturally into more stable and bioavailable water-soluble compounds. Studies have shown that the active ingredients in garlic (Allium sativum) extracts, including DADS and DATS, effectively inhibit the proliferation of cancer cells (34-38) . SAC also reportedly suppresses thegrowthof several types of cancer (39-41) . Our previous study showed that SAC inhibited the proliferation ofhuman oral cancer CAL-27 cells in vitro (42) . Moreover, SAC reportedly prevents the EMT and suppresses tumor progression inhuman oral squamous cancer cells in vitro (42) . However, thein vivo inhibitory effects of SAC on tumor growth and progression in oral cancer have not been demonstrated. The current study was undertaken to evaluate thein vivo anti-cancer effects of SAC, including the inhibition of tumor growth and progression. Immunodeficient nude mice with xenografted human oral cancer CAL-27 cells under the skin comprised the experimental model. It is demonstrated that theconsumptionof SAC significantly inhibited both the tumor growth and progression of oral cancer in this mousexenograftmodel.
Indole-3-carbinol (I3C), a natural phytochemical found inthe vegetables ofthe cruciferous family, has been shown to suppress
the proliferation of cancer cells of breast, colon, prostate, and endo- metrium by targeting multiple signaling pathways. 2–5 In addition, I3C shows a synergistic effect when combined with 1,3-tetradeca- noyl phorbolacetate plus CaCl 2 against oral squamous cell carci- noma cell lines. 6 However, there are several drawbacks for I3C as an anticancer agent. First, the effective concentration of I3C to ex- ert its antitumor activity is between 50 and 100 l M, which is impractical in vivo. Second, the chemical instability of I3C and vul- nerability to acid-catalyzed conversion into a variety of derivatives inthe stomach decrease its antitumor activity. 7 Third, the inability to reliably monitor I3C concentration in plasma limits its pharma- cokinetic anaylsis. 8 Consequently, the structural modiﬁcation of I3C or 3,3 0 -diindolylmethane attracted many researchers to devel- op novel indole derivatives with improved potency. 5,9 Among these derivatives, OSU-A9, an acid-stable analogue with higher apoptosis-inducing potency was synthesized. 10 OSU-A9 has been reported to be active against cancers of prostate, breast and liver in vitro, and has inhibited tumor growthof these cancers in xeno- graft animal models. Importantly, the repeated daily administra- tion of OSU-A9 to athymic nude mice in these experiments was well tolerated. 10–12 Inthe present study, we compared the
One previous report showed that T. sinensis leaf extracts were cytotoxic to humanlung adenocarcinoma cells A549.
In this study, we further explored the cytotoxicity of TSL2, which had the highest anti-ovarian cancer cell activity among different extraction fractions from the leave extracts of T. sinensis, on different cancer cells derived from ovarian cancer (PA-1 and SKOV3), cervical cancer (HeLa and HeLa S3), and endometrial cancer (RL95-2). Thegrowth inhibition for various cancer cell lines, determined by cell survival assay, is shown in Table 1. Twenty-four hours after treatment with 1, 10, and 100 μg/ml of TSL2, we found that TSL2 had the most potent activities against ovarian cancer cells PA-1 and SKOV3, with IC50 of 11.0 and 26.4 μg/ml, respectively. In contrast, under the same dosage and time period, TSL2 had a very low cytotoxicity on cervical cancer cells HeLa and HeLa S3 as well as endometrial cancer cells RL95-2. Therefore, we chose SKOV3, which was derived from the most common type ovarian cancer, epithelial ovarian cancer, to further study the antitumor mechanism of TSL2 in vitro and in vivo.
Ferruginol Inhibited Human NSCLC CellGrowth via a Caspase-Dependent Pathway
Activation of caspase family proteins plays a crucial role in apoptosis. Two main pathways, namely, the intrinsic and extrinsic pathways, are involved in caspase-related apopto- sis. To investigate the molecular mechanisms underlying ferruginol-induced A549 and CL1-5 cell apoptosis, apopto- sis-related proteins were examined via western blot analy- ses. The results ofthe western blot analyses revealed that the cleaved forms of caspase 3, 8, 9, and poly(ADP-ribose) polymerase (PARP) were activated after ferruginol treat- ment intheA549 and CL1-5 cell lines (Figure 4). Based on these results, ferruginol may induce apoptosis via both the intrinsic and extrinsic pathways. Moreover, the expression ofthe anti-apoptotic protein Bcl-2 was decreased, while the expression ofthe pro-apoptotic protein Bax was elevated, after ferruginol treatment in both lung cancer cell lines (Figure 5A). The Bcl-2/Bax ratio is also an important index to assess the regulatory effect of these proteins inthecell death process. As shown in Figure 5B, the Bcl-2/Bax ratios ofA549 and CL1-5 cells were decreased ina dose-depen- dent manner after ferruginol treatment. InA549 cells, the Bcl-2/Bax ratios were 1, 0.64, 0.37, and 0.30 for 0, 40, 60, and 80 µM ferruginol treatment groups, respectively. The similar tendency was also found in CL1-5 cells and indi- cated that ferruginol decreased the Bcl-2/Bax ratio as well as induced the mitochondrial dysfunction inlung cancer cell lines. In contrast, the activities of caspase family pro- teins were also regulated by IAP family proteins. Thus, the expression of survivin and XIAP were also determined using western blot analyses. As shown in Figure 5A, the expression of IAP family proteins was decreased after fer- ruginol treatment inA549 and CL1-5 cells. Additionally, the expression of Smac was enhanced after ferruginol treat- ment in 2 cell lines. These results indicated that ferruginol exhibited caspase-dependent mitochondrial apoptotic path- way activation inthe 2 cell lines.
Lapatinib, an orally administered small-molecule tyrosine kinase inhibitor targeting epidermal growth factor receptors (EGFR) and Her2/Neu, has been widely accepted inthe treatment of breast cancer. In this study, we found that lapatinib induced cytotoxicity inhuman hepatoma Huh7, HepG2 and HA22T cells. For the mode ofcell death, we found lapatinib induced a higher percent of dead cells and a lower percent of hypodiploid cells, suggesting non-apoptotic cell death in lapatinib-treated hepatoma cells.
Inthe present study, H520 and H226 human SqCC cancer cell
lines were treated with different concentrations of pterostil- bene for 24 and 48 h. As illustrated in Fig. 1A, pterostilbene induced cytotoxicity inhuman SqCC cancer cell lines ina dose-dependent manner. Notably, these two SqCC cell lines exhibited different sensitivities to pterostilbene; the IC50 values of pterostilbene for H520 cells were 47.7±5.3 and 31.4±4.6 µM at 24 and 48 h, respectively, while the IC50 values for H226 cells were >50 and 44.3±3.7 µM at 24 and 48 h, respectively. In addition, thecell morphology and shape were assessed using an inverted microscope; this assessment indicated apoptotic morphological changes, including cell shrinkage and cyto- plasmic blebbing, inthe treated cells (Fig. 1B). The results demonstrated that the H520 cell line was highly sensitive to pterostilbene treatment; therefore H520 was selected for the subsequent analysis and evaluation ofthe cytotoxic potency of pterostilbene.
Taken together, although the precise roles of HOXA5 inlung cancer progression remain to be elucidated, we showed here that HOXA5 might act as a suppressor of metastasis during lung tumour progression, at least partly through the inhibition of calcium-mediated actin cytoskeleton polymerisation. However, the detailed molecular mechanisms underlying this inhibition require further investigation. Tetracyclin-inducible system for HOXA5 expression in NSCLC cells would be another good approach to clarify the expression levels and roles of these candidate genes inthe future studies. In addition, HOXA5 expression is positively correlated with survival in NSCLC patients, especially those with wild-type EGFR. This result suggests that HOXA5 possibly would serve as a prognostic factor in these NSCLC patients. Nevertheless, the correlation and the regulatory mechanisms between EGFR status and HOXA5 are worthy of further investigation.