Inhibition of Skin Inflammation by Scytonemin, an Ultraviolet Sunscreen Pigment.

Scytonemin is a yellow-green ultraviolet sunscreen pigment present in different genera of aquatic and terrestrial blue-green algae, including marine cyanobacteria. In the present study, the anti-inflammatory activities of scytonemin were evaluated in vitro and in vivo. Topical application of scytonemin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear swelling in BALB/c mice. The expression of tumor necrosis factor-a (TNF-a) and inducible nitric oxide synthase (iNOS) was also suppressed by scytonemin treatment in the TPA-treated ear of BALB/c mice. In addition, scytonemin inhibited lipopolysaccharide (LPS)-induced production of TNF-a and nitric oxide (NO) in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expressions of TNF-a and iNOS were also suppressed by scytonemin in LPS-stimulated RAW 264.7 cells. Further study demonstrated that LPS-induced NF-kB activity was significantly suppressed by scytonemin treatment in RAW 264.7 cells. Our results also showed that the degradation of IkBa and nuclear translocation of the p65 subunit were blocked by scytonemin in LPS-stimulated RAW 264.7 cells. Collectively, these results suggest that scytonemin inhibits skin inflammation by blocking the expression of inflammatory mediators, and the anti-inflammatory effect of scytonemin is mediated, at least in part, by down-regulation of NF-kB activity. Our results also suggest that scytonemin might be used as a multi-function skin care ingredient for UV protection and anti-inflammation.

Small activating RNA induced expression of VHL gene in renal cell carcinoma.

Recent studies have reported that chemically synthesized double-stranded RNAs (dsRNAs), also known as small activating RNA (saRNAs), can specifically induce gene expression by targeting promoter sequences by a mechanism termed RNA activation (RNAa). In the present study, we designed 4 candidate saRNAs targeting the Von Hippel-Lindau (VHL) gene promoter. Among these saRNAs, dsVHL-821 significantly inhibited cell growth by up-regulating VHL at both the mRNA and protein levels in renal cell carcinoma 769-P cells. Functional analysis showed that dsVHL-821 induced apoptosis by increasing p53, decreasing Bcl-xL, activating caspase 3/7 and poly-ADP-ribose polymerase in a dose-dependent manner. Chromatin immunoprecipitation analysis revealed that dsVHL-821 increased the enrichment of Ago2 and RNA polymerase II at the dsVHL-821 target site. In addition, Ago2 depletion significantly suppressed dsVHL-821-induced up-regulation of VHL gene expression and related effects. Single transfection of dsVHL-821 caused long-lasting (14 days) VHL up-regulation. Furthermore, the activation of VHL by dsVHL-821 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 4 (H4ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) and lysine 27 (H3K27me2) in the dsVHL-821 target region. Taken together, these results demonstrate that dsVHL-821, a novel saRNA for VHL, induces the expression of the VHL gene by epigenetic changes, leading to inhibition of cell growth and induction of apoptosis, and suggest that targeted activation of VHL by dsVHL-821 may be explored as a novel treatment of renal cell carcinoma.

Development of Therapeutic dsP21-322 for Cancer Treatment.

Small activating RNAs (saRNAs) are a class of artificially designed short duplex RNAs targeted at the promoter of a particular gene to upregulate its expression via a mechanism known as RNA activation (RNAa) and hold great promise for treating a wide variety of diseases including those undruggable by conventional therapies. The therapeutic benefits of saRNAs have been demonstrated in a number of preclinical studies carried out in different disease models including cancer. With many tumor suppressor genes (TSGs) downregulated due to either epigenetic mechanisms or haploinsufficiency resulting from deletion/mutation, cancer is an ideal disease space for saRNA therapeutics which can restore the expression of TSGs via epigenetic reprogramming. The p21WAF1/CIP gene is a TSG frequently downregulated in cancer and an saRNA for p21WAF1/CIP known as dsP21-322 has been identified to be a sequence-specific p21WAF1/CIP activator in a number of cancer types. In this chapter, we review preclinical development of medicinal dsP21-322 for cancer, especially prostate cancer and bladder cancer, and highlight its potential for further clinical development.

miR-6734 Up-Regulates p21 Gene Expression and Induces Cell Cycle Arrest and Apoptosis in Colon Cancer Cells.

Recently, microRNAs have been implicated in the regulation of gene expression in terms of both gene silencing and gene activation. Here, we investigated the effects of miR-6734, which has a sequence homology with a specific region of p21WAF1/CIP1 (p21) promoter, on cancer cell growth and the mechanisms involved in this effect. miR-6734 up-regulated p21 expression at both mRNA and protein levels and chromatin immunoprecipitation analysis using biotin-labeled miR-6734 confirmed the association of miR-6734 with p21 promoter. Moreover, miR-6734 inhibited cancer cell growth and induced cell cycle arrest and apoptosis in HCT-116 cells, which was abolished by knockdown of p21. The phosphorylation of Rb and the cleavage of caspase 3 and PARP were suppressed by miR-6734 transfection in HCT-116 cells and these effects were also reversed by p21 knockdown. In addition, miR-6734 transfection caused prolonged induction of p21 gene and modification of histones in p21 promoter, which are typical aspects of a phenomenon referred to as RNA activation (RNAa). Collectively, our results demonstrated that miR-6734 inhibits the growth of colon cancer cells by up-regulating p21 gene expression and subsequent induction of cell cycle arrest and apoptosis, suggesting its role as an important endogenous regulator of cancer cell proliferation and survival.

Cardiovascular protective effect of glabridin: Implications in LDL oxidation and inflammation.

Atherosclerosis is one of the most common causes of death in Western countries and now considered as a chronic inflammatory disease in broad outline. Glaridin, a flavonoid isolated from licorice root, has been shown to exert a variety of biological activities, including antimicrobial, antioxidant, anti-inflammatory and cardiovascular protective effects. Among these, the most extensive research area in the past two decades was a cardiovascular protection-related activity of glabridin. The protective effect of glabridin on LDL oxidation, which is one of the important processes involved in the development of atherosclerosis, was demonstrated in vitro and in vivo and the mechanisms involved in this process were established well. Structure-activity relationship of glabridin derivatives on LDL oxidation was also reported. In addition, the inhibitory effects of glabridin on early inflammatory processes, including the expression of adhesion molecules on endothelial cells and the activation of macrophages and dendritic cells, were also demonstrated previously. In this review, we summarized the cardiovascular protection-related activities of glabridin and the mechanism of action involved in these activities. Collectively, it is hoped that glabridin or glabridin derivatives might be used as a therapeutic agent for the treatment of cardiovascular diseases in the future.

Hypothemycin inhibits tumor necrosis factor-α production by tristetraprolin-dependent down-regulation of mRNA stability in lipopolysaccharide-stimulated macrophages.

Hypothemycin, a resorcylic acid lactone polyketide, has been shown to inhibit oncogenic ras-transformation and T cell activation. In the present study, we investigated the effect of hypothemycin on tumor necrosis factor-α (TNF-α) production in macrophages and the molecular mechanisms involved in this effect. Hypothemycin potently suppressed the TNF-α production without affecting nitric oxide production in lipopolysaccharide (LPS)-stimulated macrophages. However, hypothemycin had no effect on the activity of TNF-α-converting enzyme, a key enzyme for converting membrane-bound pro-TNF-α into soluble TNF-α. Further study demonstrated that the stability of TNF-α mRNA was decreased by hypothemycin treatment. In addition, hypothemycin suppressed LPS-induced phosphorylation of p38 MAPK and ERK. Moreover, knockdown of tristetraprolin (TTP), which is an important trans-acting regulator of TNF-α mRNA stability and downstream target of p38 MAPK and ERK, reversed hypothemycin-mediated inhibition of TNF-α mRNA expression. Collectively, our results suggest that hypothemycin suppresses TNF-α production by TTP-dependent destabilization of TNF-α mRNA and this is mediated, at least in part, by blocking the activation of p38 MAPK and ERK.

Inducing gene expression by targeting promoter sequences using small activating RNAs.

Vector-based systems comprised of exogenous nucleic acid sequences remain the standard for ectopic expression of a particular gene. Such systems offer robust overexpression, but have inherent drawbacks such as the tedious process of construction, excluding sequences (e.g. introns and untranslated regions) important for gene function and potential insertional mutagenesis of host genome associated with the use of viral vectors. We and others have recently reported that short double-stranded RNAs (dsRNAs) can induce endogenous gene expression by targeting promoter sequences in a phenomenon referred to as RNA activation (RNAa) and such dsRNAs are termed small activating RNAs (saRNAs). To date, RNAa has been successfully utilized to induce the expression of different genes such as tumor suppressor genes. Here, we describe a detailed protocol for target selection and dsRNA design with associated experiments to facilitate RNAa in cultured cells. This technique may be applied to selectively activate endogenous gene expression for studying gene function, interrogating molecular pathways and reprogramming cell fate.

Agelasine D suppresses RANKL-induced osteoclastogenesis via down-regulation of c-Fos, NFATc1 and NF-κB.

In the present study, we investigated the effect of agelasine D (AD) on osteoclastogenesis. Treatment of bone marrow macrophages (BMMs) with receptor activator of nuclear factor κB ligand (RANKL) resulted in a differentiation of BMMs into osteoclasts as evidenced by generation of tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated cells and formation of pits in calcium phosphate-coated plates. However, RANKL-induced osteoclastogenesis was significantly suppressed by AD treatment. We also confirmed the increased mRNA and protein expression of osteoclastic markers, such as TRAP, cathepsin K and matrix metalloproteinase-9, during RANKL-induced osteoclast differentiation and this was down-regulated by AD treatment. Moreover, AD treatment significantly suppressed RANKL-induced mRNA expression of DC-STAMP and OC-STAMP and cell fusion of TRAP-positive mononuclear osteoclast precursors. In addition, AD suppressed RANKL-induced expression of transcription factors, c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are important transcription factors involved in differentiation of BMMs into osteoclasts. Furthermore, RANKL-induced phosphorylation of extracellular signal-related kinase (ERK) and activation of NF-κB were also inhibited by AD treatment. Collectively, these results suggest that AD inhibits RANKL-induced osteoclastogenesis by down-regulation of multiple signaling pathways involving c-Fos, NFATc1, NF-κB and ERK. Our results also suggest that AD might be a potential therapeutic agent for prevention and treatment of osteoporosis.

Hepatoprotective effect of aged black garlic extract in rodents.

In this study, we investigated the hepatoprotective effects of aged black garlic (ABG) in rodent models of liver injury. ABG inhibited carbon tetrachloride-induced elevation of aspartate transaminase (AST) and alanine transaminase (ALT), which are markers of hepatocellular damage, in SD rats. D-galactosamineinduced hepatocellular damage was also suppressed by ABG treatment. However, ABG does not affect the elevation of alkaline phosphatase (ALP), a marker of hepatobilliary damage, in rats treated with carbon tetrachloride or D-galactosamine. We also examined the effect of ABG on high-fat diet (HFD)-induced fatty liver and subsequent liver damage. ABG had no significant effect on body weight increase and plasma lipid profile in HFD-fed mice. However, HFD-induced increase in AST and ALT, but not ALP, was significantly suppressed by ABG treatment. These results demonstrate that ABG has hepatoprotective effects and suggest that ABG supplementation might be a good adjuvant therapy for the management of liver injury.

Targeted induction of endogenous NKX3-1 by small activating RNA inhibits prostate tumor growth.

BACKGROUND: RNA activation (RNAa) is a small RNA-mediated gene regulation mechanism by which expression of a particular gene can be induced by targeting its promoter using small double-stranded RNA also known as small activating RNA (saRNA). We used saRNA as a molecular tool to examine NKX3-1's role as a tumor suppressor and tested in vitro and in vivo antitumor effects of NKX3-1 induction by saRNA. MATERIALS AND METHODS: NKX3-1 saRNA was transfected into human prostate cancer cells including LNCaP, CWR22R, PC-3, CWR22RV1, DuPro, LAPC4, and DU145. The transfected cells were used for analysis of gene expression by RT-PCR and immunoblotting, proliferation, apoptosis and cell cycle distribution. PC-3 xenograft models were established in immunocompromised mice and treated with NKX3-1 saRNA. RESULTS: NKX3-1 saRNA induced NKX3-1 expression in different prostate cancer cell lines, resulting in inhibited cell proliferation and survival, cell cycle arrest and apoptotic cell death. These effects were partly mediated by NKX3-1's regulation of several downstream genes including the upregulation of p21 and p27, and the inhibition of VEGFC expression. Treatment of mouse xenograft prostate tumors with intratumoral delivery of NKX3-1 saRNA formulated in lipid nanoparticles significantly inhibited tumor growth and prolonged animal survival. CONCLUSIONS: By revealing several important target genes of NKX3-1, our findings corroborated NKX3-1's role as a tumor suppressor gene through direct regulation of the cell cycle and growth/survival pathways. This study also validated the therapeutic potential of saRNA for the treatment of prostate cancer via targeted activation of tumor suppressor genes.

Differential anti-inflammatory and analgesic effects by enantiomers of zaltoprofen in rodents.

In the present study, we investigated the effect of zaltoprofen enantiomers on inflammation and pain and compared their effect with racemic zaltoprofen. S(+)-zaltoprofen potently inhibited the inflammatory response in carrageenan-induced paw edema model, whereas R(-)-zaltoprofen did not. Moreover, the anti-inflammatory effect of S(+)-zaltoprofen was stronger than that of racemic zaltoprofen, suggesting that S(+)-zaltoprofen is an active component of racemic zaltoprofen in terms of anti-inflammatory activity. In contrast, the results of acetic acid-induced writhing model demonstrated that no significant analgesic effect was observed by racemic zaltoprofen and zaltoprofen enantiomers at doses used in carrageenan-induced paw edema model. However, racemic zaltoprofen and zaltoprofen enantiomers all exerted an analgesic effect at higher doses, which is inconsistent with the result of carrageenan-induced paw edema model. Gastric ulcers induced by racemic zaltoprofen and zaltoprofen enantiomers were minimal. Taken together, these results suggest that S(+)-zaltoprofen is a potent and active anti-inflammatory component of racemic zaltoprofen, but both S(+)-zaltoprofen and R(-)-zaltoprofen might seem to contribute to the analgesic effect of racemic zaltoprofen.

An orthotopic bladder tumor model and the evaluation of intravesical saRNA treatment.

We present a novel method for treating bladder cancer with intravesically delivered small activating RNA (saRNA) in an orthotopic xenograft mouse bladder tumor model. The mouse model is established by urethral catheterization under inhaled general anesthetic. Chemical burn is then introduced to the bladder mucosa using intravesical silver nitrate solution to disrupt the bladder glycosaminoglycan layer and allows cells to attach. Following several washes with sterile water, human bladder cancer KU-7-luc2-GFP cells are instilled through the catheter into the bladder to dwell for 2 hours. Subsequent growth of bladder tumors is confirmed and monitored by in vivo bladder ultrasound and bioluminescent imaging. The tumors are then treated intravesically with saRNA formulated in lipid nanoparticles (LNPs). Tumor growth is monitored with ultrasound and bioluminescence. All steps of this procedure are demonstrated in the accompanying video.

Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth.

Practical methods for enhancing protein production in vivo remain a challenge. RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression. This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing. Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21(WAF1/CIP1) (p21). In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2'-fluoro-modified derivative (dsP21-322-2'F) into lipid nanoparticles (LNP) for intravesical delivery. LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA. We confirm p21 induction, cell-cycle arrest, and apoptosis in vitro following treatment with LNP-formulated dsP21-322-2'F (LNP-dsP21-322-2'F) or one of its nonformulated variants. Both 2'-fluoro modification and LNP formulation also improve duplex stability in urine. Intravesical delivery of LNP-dsP21-322-2'F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer. LNP-dsP21-322-2'F treatment also facilitates p21 activation in vivo leading to regression/disappearance of tumors in 40% of the treated mice. Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes.

Targeted p21WAF1/CIP1 activation by RNAa inhibits hepatocellular carcinoma cells.

RNA activation (RNAa) is a mechanism of gene activation triggered by promoter-targeted small double-stranded RNA (dsRNA), also known as small activating RNA (saRNA). p21(WAF1/CIP1) (p21) is a putative tumor suppressor gene due to its role as a key negative regulator of the cell cycle and cell proliferation. It is frequently downregulated in cancer including hepatocellular carcinoma (HCC), but is rarely mutated or deleted, making it an ideal target for RNAa-based overexpression to restore its tumor suppressor function. In the present study, we investigated the antigrowth effects of p21 RNAa in HCC cells. Transfection of a p21 saRNA (dsP21-322) into HepG2 and Hep3B cells significantly induced the expression of p21 at both the mRNA and protein levels, and inhibited cell proliferation and survival. Further analysis of dsP21-322 transfected cells revealed that dsP21-322 arrested the cell cycle at the G(0)/G(1) phase in HepG2 cells but at G(2)/M phase in Hep3B cells which lack functional p53 and Rb genes, and induced both early and late stage apoptosis by activating caspase 3 in both cell lines. These results demonstrated that RNAa of p21 has in vitro antigrowth effects on HCC cells via impeding cell cycle progression and inducing apoptotic cell death. This study suggests that targeted activation of p21 by RNAa may be explored as a novel therapy for the treatment of HCC.

Gene expression profiling of KBH-A42, a novel histone deacetylase inhibitor, in human leukemia and bladder cancer cell lines.

The aim of this study was to investigate the anti-tumor activity of KBH-A42, a novel synthetic histone deacetylase (HDAC) inhibitor. KBH-A42 was shown to significantly suppress the proliferation of all 14 human cancer cell lines tested. Among these cell lines, the human leukemia cell line K562 was the most sensitive, whereas the UM-UC-3 bladder cancer cells were the least sensitive. Additionally, in a human tumor xenograft model using Balb/c nude mice, KBH-A42 was shown to significantly inhibit the growth of K562 tumors, although it only slightly inhibited the growth of UM-UC-3 tumors. The results of flow cytometry analysis and caspase 3/7 activation assays showed that the growth inhibition of K562 cells by KBH-A42 was mediated, at least in part, by the induction of apoptosis, but its growth inhibitory effects on UM-UC-3 cells were not mediated by apoptotic induction. In an effort to gain insight into the mechanism by which KBH-A42 inhibits the growth of cancer cells, a microarray analysis was conducted. Four genes were selected from the genes that were down-regulated or up-regulated by KBH-A42 and confirmed via reverse transcription-polymerase chain reaction as follows: Harakiri (HRK), tumor necrosis factor receptor superfamily, member 10b (TNFRSF10B), PYD and CARD domain containing protein gene (PYCARD) and tumor necrosis factor receptor superfamily, member 8 (TNFRSF8). Collectively, the in vitro and in vivo results suggested that KBH-A42 exhibits anti-cancer activity, but various types of cells may be regulated differentially by KBH-A42.

Is apparent diffusion coefficient reliable and accurate for monitoring effects of antiangiogenic treatment in a longitudinal study?

PURPOSE: To evaluate the reliability and accuracy of the apparent diffusion coefficient (ADC) for monitoring antiangiogenic treatment in a longitudinal study. MATERIALS AND METHODS: Tumor volume and ADC were monitored by T2-weighted magnetic resonance imaging (MRI) and diffusion-weighted MRI, respectively, in 18 mice with angiogenesis-dependent tumors (U118MG) before (day 0) and after 2, 7, 14, and 21 days of administration of the antiangiogenic agent sunitinib maleate (n = 12) or vehicle (n = 6). Percent changes in tumor volume and ADC were calculated and correlations between tumor volume and ADC were evaluated. RESULTS: Tumor volume and ADC showed a negative correlation at 69 of the 72 (96%) follow-up measurements. In the 13 mice with tumor regrowth, ADC started to decrease before (27%) or at the same time (73%) as tumor regrowth. Pretreatment ADC and percent change in ADC change on days 0-2 were similar in mice with positive and negative responses to treatment (0.851 vs. 0.999, 24% vs. 16%). Percent change of ADC showed significant negative correlation with percent change in tumor volume in both the control (r = -0.69) and treated (r = -0.65) groups. CONCLUSION: Percent change in ADC is a reliable and accurate marker for monitoring the effects of antiangiogenic treatment, whereas pretreatment ADC and early changes in ADC (ie, days 0-2) are limited in predicting treatment outcome.

Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells.

Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose- and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase­3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation.

Methanolic Extract Isolated from Root of Lycoris aurea Inhibits Cancer Cell Growth and Endothelial Cell Tube Formation In Vitro.

In this study, we investigated the effect of methanolic extract isolated from the root of Lycoris aurea (LA) on the growth of cancer cells and the tube formation activity of endothelial cells. Various cancer cells were treated with LA at doses of 0.3, 1, 3, 10 or 30 µg/ml and LA significantly suppressed the growth of several cancer cell lines, including ACHN, HCT-15, K-562, MCF-7, PC-3 and SK-OV-3, in a dose-dependent manner. We also found that LA induced cell cycle arrest at G2/M phase in ACHN renal cell adenocarcinoma cells. Further study demonstrated that LA concentration-dependently inhibited the tube formation, which is a widely used in vitro model of reorganization stage of angiogenesis, in human umbilical vein endothelial cells. Collectively, these results show that LA inhibits the growth of cancer cells and tube formation of endothelial cells and the growth-inhibitory effect of LA might be mediated, at least in part, by blocking cell cycle progression.

Lipid-soluble ginseng extract induces apoptosis and G0/G1 cell cycle arrest in NCI-H460 human lung cancer cells.

This study was performed to elucidate the anticancer mechanism of a lipid-soluble ginseng extract (LSGE) by analyzing induction of apoptosis and arrest of cell cycle progression using the NCI-H460 human lung cancer cell line. Proliferation of NCI-H460 cells was potently inhibited by LSGE in a dose-dependent manner. The cell cycle arrest at the G0/G1 phase in NCI-H460 cells was induced by LSGE. The percentage of G0/G1 phase cells significantly increased, while that of S phase cells decreased after treatment with LSGE. The expression levels of cyclin-dependent kinase2 (CDK2), CDK4, CDK6, cyclin D3 and cyclin E related to G0/G1 cells progression were also altered by LSGE. In addition, LSGE-induced cell death occurred through apoptosis, which was accompanied by increasing the activity of caspases including caspase-8, caspase-9 and caspase-3. Consistent with enhancement of caspase activity, LSGE increased protein levels of cleaved caspase-3, caspase-8, caspase-9, and poly-ADP-ribose polymerase (PARP). These apoptotic effects of LSGE were inhibited by the pan-caspase inhibitor Z-VAD-fmk. These findings indicate that LSGE inhibits NCI-H460 human lung cancer cell growth by cell cycle arrest at the G0/G1 phase and induction of caspase-mediated apoptosis.

Feasibility of FAIR imaging for evaluating tumor perfusion.

PURPOSE: To evaluate the feasibility of flow-sensitive alternating inversion recovery (FAIR) for measuring blood flow in tumor models. MATERIALS AND METHODS: In eight mice tumor models, FAIR and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed. The reliability for measuring blood flow on FAIR was evaluated using the coefficient of variation of blood flow on psoas muscle. Three regions of interest (ROIs) were drawn in the peripheral, intermediate, and central portions within each tumor. The location of ROI was the same on FAIR and DCE-MR images. The correlation between the blood flow on FAIR and perfusion-related parameters on DCE-MRI was evaluated using the Pearson correlation coefficient. RESULTS: The coefficient of variation for measuring blood flow was 9.8%. Blood flow on FAIR showed a strong correlation with Kep (r = 0.77), percent relative enhancement (r = 0.73), and percent enhancement ratio (r = 0.81). The mean values of blood flow (mL/100 g/min) (358 vs. 207), Kep (sec(-) (1)) (7.46 vs. 1.31), percent relative enhancement (179% vs. 134%), and percent enhancement ratio (42% vs. 26%) were greater in the peripheral portion than in the central portion (P < 0.01). CONCLUSION: As blood flow measurement on FAIR is reliable and closely related with that on DCE-MR, FAIR is feasible for measuring tumor blood flow.