Gadolinium-Based Magnetic Resonance Theranostic Agent with Gallic Acid as an Anti-Neuroinflammatory and Antioxidant Agent.

Studies in the field have actively pursued the incorporation of diverse biological functionalities into gadolinium-based contrast agents, aiming at the amalgamation of MRI imaging and therapeutic capabilities. In this research, we present the development of Gd-Ga, an anti-neuroinflammatory MR contrast agent strategically designed to target inflammatory mediators for comprehensive imaging diagnosis and targeted lesion treatment. Gd-Ga is a gadolinium complex composed of 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) conjugated with gallic acid (3,4,5-trihydroxybenzoic acid). Upon intravenous administration in LPS-induced mouse models, Gd-Ga demonstrated a remarkable three-fold increase in signal-to-noise (SNR) variation compared to Gd-DOTA, particularly evident in both the cortex and hippocampus 30 min post-MR monitoring. In-depth investigations, both in vitro and in vivo, into the anti-neuroinflammatory properties of Gd-Ga revealed significantly reduced protein expression levels of pro-inflammatory mediators compared to the LPS group. The alignment between in silico predictions and phantom studies indicates that Gd-Ga acts as an anti-neuroinflammatory agent by directly binding to MD2. Additionally, the robust antioxidant activity of Gd-Ga was confirmed by its effective scavenging of NO and ROS. Our collective findings emphasize the immense potential of this theranostic complex, where a polyphenol serves as an anti-inflammatory drug, presenting an exceptionally efficient platform for the diagnosis and treatment of neuroinflammation.

Nonsteroidal Anti-Inflammatory Drug Conjugated with Gadolinium (III) Complex as an Anti-Inflammatory MRI Agent.

Studies have been actively conducted to ensure that gadolinium-based contrast agents for magnetic resonance imaging (MRI) are accompanied by various biological functions. A new example is the anti-inflammatory theragnostic MRI agent to target inflammatory mediators for imaging diagnosis and to treat inflammatory diseases simultaneously. We designed, synthesized, and characterized a Gd complex of 1,4,7-tris(carboxymethylaza) cyclododecane-10-azaacetylamide (DO3A) conjugated with a nonsteroidal anti-inflammatory drug (NSAID) that exerts the innate therapeutic effect of NSAIDs and is also applicable in MRI diagnostics. Gd-DO3A-fen (0.1 mmol/kg) was intravenously injected into the turpentine oil-induced mouse model, with Gd-DO3A-BT as a control group. In the in vivo MRI experiment, the contrast-to-noise ratio (CNR) was higher and persisted longer than that with Gd-DO3A-BT; specifically, the CNR difference was almost five times at 2 h after injection. Gd-DO3A-fen had a binding affinity (Ka) of 6.68 × 106 M-1 for the COX-2 enzyme, which was 2.1-fold higher than that of fenbufen, the original NSAID. In vivo evaluation of anti-inflammatory activity was performed in two animal models. In the turpentine oil-induced model, the mRNA expression levels of inflammatory parameters such as COX-2, TNF-α, IL-1ß, and IL-6 were reduced, and in the carrageenan-induced edema model, swelling was suppressed by 72% and there was a 2.88-fold inhibition compared with the saline group. Correlation analysis between in vitro, in silico, and in vivo studies revealed that Gd-DO3A-fen acts as an anti-inflammatory theragnostic agent by directly binding to COX-2.

Flavonoid-Conjugated Gadolinium Complexes as Anti-Inflammatory Theranostic Agents.

In this study, we designed, synthesized, and evaluated gadolinium compounds conjugated with flavonoids as potential theranostic agents for the treatment of inflammation. These novel theranostic agents combine a molecular imaging agent and one of three flavonoids (galangin, chrysin, and 7-hydroxyflavone) as anti-inflammatory drugs as a single integrated platform. Using these agents, MR imaging showed contrast enhancement (>10 in CNR) at inflamed sites in an animal inflammation model, and subsequent MR imaging used to monitor the therapeutic efficacy of these integrated agents revealed changes in inflamed regions. The anti-inflammatory effects of these agents were demonstrated both in vitro and in vivo. Furthermore, the antioxidant efficacy of the agents was evaluated by measuring their reactive oxygen species scavenging properties. For example, Gd-galangin at 30 µM showed a three-fold higher ROS scavenging of DPPH. Taken together, our findings provide convincing evidence to indicate that flavonoid-conjugated gadolinium compounds can be used as potentially efficient theranostic agents for the treatment of inflammation.

Topical Administration of a Novel Acetylated Tetrapeptide Suppresses Vascular Permeability and Immune Responses and Alleviates Atopic Dermatitis in a Murine Model.

Although the pathogenesis of atopic dermatitis (AD) remains to be fully deciphered, skin barrier abnormality and immune dysregulation are known to be involved. Recently, the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has also been implicated in the pathogenesis of this multifactorial chronic inflammatory skin disorder. Previously, we showed that a novel tetrapeptide, N-acetyl-Arg-Leu-Tyr-Glu (Ac-RLYE), inhibits angiogenesis and vascular permeability effectively by selectively antagonizing VEGFR-2. The current study aimed to investigate the pharmacological effect of Ac-RLYE on AD in vitro and in vivo. The in vitro experiments demonstrated that Ac-RLYE inhibited VEGF-induced vascular permeability in endothelial cells. Moreover, in an in vivo animal model of AD, Ac-RLYE relieved AD-like symptoms such as ear thickness and dermatitis severity scores and infiltration of immune cells, including mast cells and eosinophils. Ac-RLYE inhibited IgE secretion, restored the skin barrier protein filaggrin level, and markedly downregulated gene expression of AD-related Th1, Th2, and Th17 cytokines. Collectively, these findings suggest that Ac-RLYE would be useful for the treatment of AD and associated inflammatory skin disorders.

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents.

The purpose of this study is to assess the physicochemical properties and MRI diagnostic efficacy of two newly synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd chelates, Gd-SucL and Gd-GluL, with an asymmetric α-substituted pendant arm as potential hepatocyte-specific magnetic resonance imaging contrast agents (MRI CAs). Our findings show that fine conformational changes in the chelating arm affect the in vivo pharmacokinetic behavior of the MRI CA, and that a six-membered chelating substituent of Gd-SucL is more advantageous in this system to avoid unwanted interactions with endogenous species. Gd-SucL exhibited a general DOTA-like chelate stability trend, indicating that all chelating arms retain coordination bonding. Finally, the in vivo diagnostic efficacy of highly stable Gd-SucL as a potential hepatocyte-specific MRI CA was evaluated using T1-weighted MR imaging on an orthotopic hepatocarcinoma model.

Role of Induced Programmed Cell Death in the Chemopreventive Potential of Apigenin.

The flavonoid apigenin (4',5,7-trihydroxyflavone), which is one of the most widely distributed phytochemicals in the plant kingdom, is one of the most thoroughly investigated phenolic components. Previous studies have attributed the physiological effects of apigenin to its anti-allergic, antibacterial, antidiabetic, anti-inflammatory, antioxidant, antiviral, and blood-pressure-lowering properties, and its documented anticancer properties have been attributed to the induction of apoptosis and autophagy, the inhibition of inflammation, angiogenesis, and cell proliferation, and the regulation of cellular responses to oxidative stress and DNA damage. The most well-known mechanism for the compound's anticancer effects in human cancer cell lines is apoptosis, followed by autophagy, and studies have also reported that apigenin induces novel cell death mechanisms, such as necroptosis and ferroptosis. Therefore, the aim of this paper is to review the therapeutic potential of apigenin as a chemopreventive agent, as well as the roles of programmed cell death mechanisms in the compound's chemopreventive properties.

In Vivo Efficacy of Imatinib Mesylate, a Tyrosine Kinase Inhibitor, in the Treatment of Chemically Induced Dry Eye in Animal Models.

Purpose: Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface accompanied by ocular discomfort, visual disturbance, tear film instability, and ocular surface inflammation. In the present study, we evaluated the efficacy of the tyrosine kinase inhibitor imatinib mesylate for the treatment of DED. Methods: Experimental models of DED were generated in Sprague Dawley rats using a combination of benzalkonium chloride (BAC) with atropine sulfate and in New Zealand White rabbits using BAC. The animals were treated twice daily with eye drops of vehicle, imatinib (0.01%-0.3%), or a positive control (Restasis). The improvement in DED due to imatinib was assessed by staining with fluorescein, lissamine green, impression cytology, and histological analysis. In addition, immunofluorescence staining was performed at the end of the study to evaluate the inflammatory response in the ocular surface. Results: Topical application of imatinib significantly reduced ocular surface damage compared with vehicle-treated animals. Imatinib restored the morphology and structure of the conjunctival epithelium and reduced the recruitment of immune cells in the corneal epithelium. Furthermore, imatinib significantly reduced the impression cytology score, thus demonstrating that imatinib prevents the loss of goblet cells in DED animal models. The therapeutic efficacy of imatinib was similar to or better than that of cyclosporine treatment. Conclusions: In this study, we provide an animal in vivo proof of concept of the therapeutic potential of imatinib for the treatment of DED. Translational Relevance: With this study we show the possibility of developing imatinib as a new ophthalmic drop to treat DED.

Synthesis, Characterization, and Anticancer Activity of Benzothiazole Aniline Derivatives and Their Platinum (II) Complexes as New Chemotherapy Agents.

We describe the synthesis, characterization, molecular modeling, and in vitro anticancer activity of three benzothiazole aniline (BTA) ligands and their corresponding platinum (II) complexes. We designed the compounds based on the selective antitumor properties of BTA, along with three types of metallic centers, aiming to take advantage of the distinctive and synergistic activity of the complexes to develop anticancer agents. The compounds were characterized using nuclear magnetic resonance spectrometry, Fourier transform infrared spectroscopy, mass spectrometry, elemental analysis, and tested for antiproliferative activity against multiple normal and cancerous cell lines. L1, L2, and L1Pt had better cytotoxicity in the liver, breast, lung, prostate, kidney, and brain cells than clinically used cisplatin. Especially, L1 and L1Pt demonstrated selective inhibitory activities against liver cancer cells. Therefore, these compounds can be a promising alternative to the present chemotherapy drugs.

Therapeutic Efficacy of a Novel Acetylated Tetrapeptide in Animal Models of Age-Related Macular Degeneration.

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.

Novel SIRT Inhibitor, MHY2256, Induces Cell Cycle Arrest, Apoptosis, and Autophagic Cell Death in HCT116 Human Colorectal Cancer Cells.

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

Gd-Complex of a Rosmarinic Acid Conjugate as an Anti-Inflammatory Theranostic Agent via Reactive Oxygen Species Scavenging.

Rosmarinic acid (RosA), an important polyphenol, is known for its antioxidant and anti-inflammatory activities. However, its application in theranostics has been rarely reported. Therefore, a new single-molecule anti-inflammatory theranostic compound containing RosA would be of great interest. A gadolinium (Gd) complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and RosA (Gd(DO3A-RosA)(H2O)) was synthesized and examined for use as a single-molecule theranostic agent. Its kinetic stability is comparable to that of clinically used macrocyclic magnetic resonance imaging contrast agents. In addition, its relaxivity is higher than that of structurally analogous Gd-BT-DO3A. This agent was evaluated for inflammatory targeting magnetic resonance contrast and showed strong and prolonged enhancement of imaging in inflamed tissues of mice. The theranostic agent also possesses antioxidant and anti-inflammatory activities, as evidenced by reactive oxygen species scavenging, superoxide dismutase activity, and inflammatory factors. The novel RosA-conjugated Gd complex is a promising theranostic agent for the imaging of inflamed tissues, as well as for the treatment of inflammation and oxidative stress.

Gadolinium-Based Neuroprognostic Magnetic Resonance Imaging Agents Suppress COX-2 for Prevention of Reperfusion Injury after Stroke.

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T1 molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.

Roles of folate in skeletal muscle cell development and functions.

Folate is the generic term for both naturally occurring food folate and folic acid, the fully oxidized monoglutamate form of the vitamin that is used in dietary supplements and fortified foods. It is a water-soluble vitamin B9 and is important for health, growth, and development. As a precursor of various cofactors, folate is required for one-carbon donors in the synthesis of DNA bases and other essential biomolecules. A lack of dietary folate can lead to folate deficiency and can therefore result in several health problems, including macrocytic anemia, elevated plasma homocysteine, cardiovascular disease, birth defects, carcinogenesis, muscle weakness, and difficulty in walking. Several studies have implied that folate might exert a positive effect on skeletal muscle development. However, the precise effects of folate in skeletal muscle development are still poorly understood. Thus, this review provides an updated discussion of the roles of folate in skeletal muscle cell development and the effects of folic acid supplementation on the functions of skeletal muscle cells.

Surface Design of Eu-Doped Iron Oxide Nanoparticles for Tuning the Magnetic Relaxivity.

Relaxivity tuning of nanomaterials with the intrinsic T1- T2 dual-contrast ability has great potential for MRI applications. Until now, the relaxivity tuning of T1 and T2 dual-modal MRI nanoprobes has been accomplished through the dopant, size, and morphology of the nanoprobes, leaving room for bioapplications. However, a surface engineering method for the relaxivity tuning was seldom reported. Here, we report the novel relaxivity tuning method based on the surface engineering of dual-mode T1- T2 MRI nanoprobes (DMNPs), along with protein interaction monitoring with the DMNPs as a potential biosensor application. Core nanoparticles (NPs) of europium-doped iron oxide (EuIO) are prepared by a thermal decomposition method. As surface materials, citrate (Cit), alendronate (Ale), and poly(maleic anhydride- alt-1-octadecene)/poly(ethylene glycol) (PP) are employed for the relaxivity tuning of the NPs based on surface engineering, resulting in EuIO-Cit, EuIO-Ale, and EuIO-PP, respectively. The key achievement of the current study is that the surface materials of the DMNP have significant impacts on the r1 and r2 relaxivities. The correlation between the hydrophobicity of the surface material and longitudinal relaxivity ( r1) of EuIO NPs presents an exponential decay feature. The r1 relaxivity of EuIO-Cit is 13.2-fold higher than that of EuIO-PP. EuIO can act as T1- T2 dual-modal (EuIO-Cit) or T2-dominated MRI contrast agents (EuIO-PP) depending on the surface engineering. The feasibility of using the resulting nanosystem as a sensor for environmental changes, such as albumin interaction, was also explored. The albumin interaction on the DMNP shows both T1 and T2 relaxation time changes as mutually confirmative information. The relaxivity tuning approach based on the surface engineering may provide an insightful strategy for bioapplications of DMNPs and give a fresh impetus for the development of novel stimuli-responsive MRI nanoplatforms with T1 and T2 dual-modality for various biomedical applications.

Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts.

Folic acid, a water soluble B vitamin, plays an important role in cellular metabolic activities, such as functioning as a cofactor in one-carbon metabolism for DNA and RNA synthesis as well as nucleotide and amino acid biosynthesis in the body. A lack of dietary folic acid can lead to folic acid deficiency and result in several health problems, including macrocytic anemia, elevated plasma homocysteine, cardiovascular disease, birth defects, carcinogenesis, muscle weakness, and walking difficulty. However, the effect of folic acid deficiency on skeletal muscle development and its molecular mechanisms are unknown. We, therefore, investigated the effect of folic acid deficiency on myogenesis in skeletal muscle cells and found that folic acid deficiency induced proliferation inhibition and cell cycle breaking as well as cellular senescence in C2C12 myoblasts, implying that folic acid deficiency influences skeletal muscle development. Folic acid deficiency also inhibited differentiation of C2C12 myoblasts and induced deregulation of the cell cycle exit and many cell cycle regulatory genes. It inhibited expression of muscle-specific marker MyHC as well as myogenic regulatory factor (myogenin). Moreover, immunocytochemistry and Western blot analyses revealed that DNA damage was more increased in folic acid-deficient medium-treated differentiating C2C12 cells. Furthermore, we found that folic acid resupplementation reverses the effect on the cell cycle and senescence in folic acid-deficient C2C12 myoblasts but does not reverse the differentiation of C2C12 cells. Altogether, the study results suggest that folic acid is necessary for normal development of skeletal muscle cells.

MHY440, a Novel Topoisomerase Ι Inhibitor, Induces Cell Cycle Arrest and Apoptosis via a ROS-Dependent DNA Damage Signaling Pathway in AGS Human Gastric Cancer Cells.

We investigated the antitumor activity and action mechanism of MHY440 in AGS human gastric cancer cells. MHY440 inhibited topoisomerase (Topo) Ι activity and was associated with a DNA damage response signaling pathway. It exhibited a stronger anti-proliferative effect on AGS cells relative to Hs27 human foreskin fibroblast cells, and this effect was both time- and concentration-dependent. MHY440 also increased cell arrest in the G2/M phase by decreasing cyclin B1, Cdc2, and Cdc25c, and upregulating p53 and p73. MHY440 induced AGS cell apoptosis through the upregulation of Fas-L, Fas, and Bax as well as the proteolysis of BH3 interacting-domain death agonist and poly(ADP-ribose) polymerase. It also contributed to the loss of mitochondrial membrane potential. The apoptotic cell death induced by MHY440 was inhibited by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, indicating that apoptosis was caspase-dependent. Moreover, the apoptotic effect of MHY440 was reactive oxygen species (ROS)-dependent, as evidenced by the inhibition of MHY440-induced PARP cleavage and ROS generation via N-acetylcysteine-induced ROS scavenging. Taken together, MHY440 showed anticancer effects by inhibiting Topo I, regulating the cell cycle, inducing apoptosis through caspase activation, and generating ROS, suggesting that MHY440 has considerable potential as a therapeutic agent for human gastric cancer.

MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and cause of cancer-related deaths. Despite advancements in conventional therapeutic approaches to CRC, most patients with CRC die of their disease. There is a need to develop novel therapeutic agents for this malignancy. Therefore, the present study aimed to examine the anticancer effects and elucidate the underlying mechanism of MHY451 in HCT116 human colorectal cancer cells. Treatment with MHY451 inhibited cell growth in a time- and concentration-dependent manner. MHY451 increased the accumulation of cell cycle progression at the G2/M phase. This agent decreased the protein level of cyclin B1 and its activating partners, Cdc25c and Cdc2, whereas it increased the cell cycle inhibitor p21WAF/CIP. The induction of apoptosis was observed by decreased viability, cleavage of poly(ADP-ribose) polymerase (PARP), alteration in the ratio of Bax/Bcl-2 protein expression and reduction of procaspase-8 and -9. Pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, inhibited MHY451-induced apoptosis, indicating that apoptotic cell death by MHY451 was mediated through caspases. Moreover, the apoptotic effect of MHY451 was reactive oxygen species (ROS)-dependent, evidenced by the inhibition of MHY451-induced PARP cleavage and ROS generation by N-acetylcysteine-induced ROS scavenging. Taken together, these results demonstrate that MHY451 exerts anticancer effects by regulating the cell cycle, inducing apoptosis through caspase activation and generating ROS. These results suggest that MHY451 has considerable potential for chemoprevention or treatment of CRC or both.

HS-1793, a resveratrol analogue, downregulates the expression of hypoxia-induced HIF-1 and VEGF and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model.

A synthetic analogue of resveratrol, 4-(6-hydroxy-2-naphtyl)-1,3-benzenediol (HS-1793), with improved photosensitivity and stability profiles, has been recently reported to exert anticancer activity on various cancer cells. However, the molecular mechanism of action and in vivo efficacy of HS-1793 in breast cancer cells have not been fully investigated. In the present study, we evaluated the effect of HS-1793 on hypoxia-inducible factor-1α (HIF-1α), which drives angiogenesis and the growth of solid tumors, in addition to the in vivo therapeutic effects of HS-1793 on breast cancer cells. HS-1793 was found to inhibit hypoxia (1.0% oxygen)-induced HIF-1α expression at the protein level, and its inhibitory effect was more potent than that of resveratrol in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, HS-1793 reduced the secretion and mRNA expression of vascular endothelial growth factor (VEGF), a key mediator of HIF-1-driven angiogenesis, without affecting cell viability. To evaluate the anticancer effects of HS-1793 in vivo, triple-negative MDA-MB-231 breast cancer xenografts were established in nude mice. HS-1793 significantly suppressed the growth of breast cancer tumor xenografts, without any apparent toxicity. Additionally, decreases in Ki-67, a proliferation index marker, and CD31, a biomarker of microvessel density, were observed in the tumor tissue. Expression of HIF-1 and VEGF was also downregulated in xenograft tumors treated with HS-1793. These in vivo results reinforce the improved anticancer activity of HS-1793 when compared with that of resveratrol. Overall, the present study suggests that the synthetic resveratrol analogue HS-1793 is a potent antitumor agent that inhibits tumor growth via the regulation of HIF-1, and demonstrates significant therapeutic potential for solid cancers.

Resveratrol analogue, HS-1793, induces apoptotic cell death and cell cycle arrest through downregulation of AKT in human colon cancer cells.

Resveratrol, a polyphenolic compound, is a naturally occurring phytochemical and is found in a variety of plants, including grapes, berries and peanuts. It has gained much attention for its potential anticancer activity against various types of human cancer. However, the usefulness of resveratrol as a chemotherapeutic agent is limited by its photosensitivity and metabolic instability. In this study the effects of a synthetic analogue of resveratrol, HS-1793, on the proliferation and apoptotic cell death were investigated using HCT116 human colon cancer cells. Although this compound has been reported to have anticancer activities in several human cancer cell lines, the therapeutic effects of HS-1793 on human colon cancer and its mechanisms of action have not been extensively studied. HS-1793 inhibited cell growth and induced apoptotic cell death in a concentration-dependent fashion. Induction of apoptosis was determined by morphological changes, cleavage of poly(ADP-ribose) polymerase, alteration of Bax/Bcl-2 expression ratio, and caspase activations. Flow cytometric analysis revealed that HS-1793 induced G2/M arrest in the cell cycle progression in HCT116 cells. Furthermore, HS-1793 showed more potent anticancer effects in several aspects than resveratrol in HCT116 cells. In addition, HS-1793 suppressed Akt and the phosphatidylinositol-3 kinase/Akt inhibitor LY294002 was found to enhance its induction of apoptosis. Thus, these findings suggest that HS-1793 have potential as a candidate chemotherapeutic agent against human colon cancer.