Modular Access to meta-Substituted Benzenes via Mo-Catalyzed Intermolecular Deoxygenative Benzene Formation.

The substituted benzene derivatives are essential to organic synthesis, medicinal chemistry, and material science. However, the 1,3-di- and 1,3,5-trisubstituted benzenes are far less prevalent in small-molecule drugs than other substitution patterns, likely due to the lack of robust, efficient, and convenient synthetic methods. Here, we report a Mo-catalyzed intermolecular deoxygenative benzene-forming reaction of readily available ynones and allylic amines. A wide range of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted benzenes were obtained in up to 88% yield by using a commercially available molybdenum catalyst. The synthetic potential of the method was further illustrated by synthetic transformations, a scale-up synthesis, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this benzene-forming process might proceed through a Mo-catalyzed aza-Michael addition/[1,5]-hydride shift/cyclization/aromatization cascade. This strategy not only provided a facile, robust, and modular approach to various meta-substituted benzene derivatives but also demonstrated the potential of molybdenum catalysis in the challenging intermolecular deoxygenative cross-coupling reactions.

Catalytic Asymmetric Deoxygenative Cyclopropanation Reactions by a Chiral Salen-Mo Catalyst.

The catalytic asymmetric cyclopropanation reaction of alkenes with diazo compounds is a direct and powerful method to construct chiral cyclopropanes that are essential to drug discovery. However, diazo compounds are potentially explosive and often require hazardous reagents for their preparation. Here, we report on the use of 1,2-dicarbonyl compounds as safe and readily available surrogates for diazo compounds in the direct catalytic asymmetric deoxygenative cyclopropanation reaction. Enabled by a class of simple and readily accessible chiral salen-Mo catalysts, the reaction proceeded with generally good enantioselectivities and yields toward a wide range of substrates (80 examples). Preliminary mechanistic studies suggested that the proposed µ-oxo bridged dinuclear Mo(III)-species was the catalytically active species. This strategy not only provides a promising route for the synthesis of chiral cyclopropanes but also opens a new window for the potential applications of chiral salen-Mo complexes in asymmetric catalysis.

Turning waste into valuables: In situ deposition of polypyrrole on the obsolete mask for Cr(VI) removal and desalination.

The global mask consumption has been exacerbated because of the coronavirus disease 2019 (COVID-19) pandemic. Simultaneously, the traditional mask disposal methods (incineration and landfill) have caused serious environmental pollution and waste of resources. Herein, a simple and green mass-production method has been proposed to recycle carbon protective mask (CPM) into the carbon protective mask/polydopamine/polypyrrole (CPM/PDA/PPy) composite by in situ polymerization of PPy. The CPM/PDA/PPy composite was used for the removal of Cr(VI) and salt ions to produce clean water. The synergistic effect of PPy and the CPM improved the removal capability of Cr(VI). The CPM/PDA/PPy composite provided high adsorption capacity (358.68 mg g-1) and economic value (811.42 mg $-1). Consequently, the CPM/PDA/PPy (cathode) was combined with MnO2 (anode) for desalination in CDI cells, demonstrated excellent desalination capacity (26.65 mg g-1) and ultrafast salt adsorption rate (6.96 mg g-1 min-1), which was higher than conventional CDI cells. Our work proposes a new low-carbon strategy to recycle discarded masks and demonstrates their utilization in Cr(VI) removal and seawater desalination.

Fuziline Ameliorates Glucose and Lipid Metabolism by Activating Beta Adrenergic Receptors to Stimulate Thermogenesis.

Radix aconiti carmichaeli is a widely used traditional Chinese medicine that has been found to be effective in treating cardiovascular diseases and metabolic disorders. Patients with these diseases often experience a heat generation disorder, which is characterized by chilliness and can worsen the progression of the disease. This study established an in vitro screening model combining the examination of cellular mitochondrial membrane potential and mitochondrial temperature to screen drugs with thermogenic activity. After differentiation and determination of the content of characteristic metabolites of the drug-containing serum blood components, it was found that Fuziline (FZL) is the key thermogenic property in Radix aconiti carmichaeli, responsible for its thermogenic effects with a high relative importance of 33%. Experiments were conducted to evaluate the thermogenic activity of Radix aconiti carmichaeli and FZL in vivo by assessing temperature changes in various organs, including the rectum, liver, and brown adipose tissue. Moreover, the effects of intracellular ß3-adrenergic receptor (ß3-AR) agonistic effects were evaluated using transient ß3-AR transfection and dual-luciferase assay systems. The molecular mechanism by which FZL promotes thermogenesis and improves mitochondrial function was investigated by verifying the ß-adrenergic receptors (ß-AR) downstream signaling pathway. The results suggest that FZL activates ß-AR nonselectively, which in turn activates the downstream cAMP-PKA signaling pathway and leads to an increase in liver glycogenolysis and triglyceride hydrolysis, accompanied by enhancing mitochondrial energy metabolism. Consequently, the liver and brown adipose tissue receive energy to generate heat. In summary, these findings provide insight into the therapeutic application of Radix aconiti carmichaeli for metabolic disorders associated with heat generation disorders.

Screening for therapeutic targets of tumor angiogenesis signatures in 31 cancer types and potential insights.

Tumor vessel normalization can increase pericyte coverage, perfusion efficiency and immune infiltration, while reducing hypoxia, vessel leakage, CTC and metastasis. In this study, we systemically presented the expression pattern of tumor angiogenesis gene signatures in 31 cancer types and its association with immune infiltration and cancer metastasis. Specifically, READ, COAD etc. have relatively similar expression patterns with low GPAGs and high PPAGs. Patients with this expression pattern may benefit from tumor vessel normalization. COAD was selected for further investigation and we found GPAG CXCL12 was downregulated while PPAG EPHB3 was overexpressed in COAD, which were further validated using two independent colon cancer dataset. Further study indicated that CXCL12 expression was positively correlated innate inflammation pathways such as NFκB and negatively correlated with metastasis, while EPHB3 had a reverse result. Moreover, CXCL12 was positively correlated with cancer immune infiltration while EPHB3 was negatively correlated with cancer immune infiltration. Besides, the association between CXCL12/EPHB3 and mutation/CNA landscape were also explored. We also discussed the potential application of gut microbiota in cancer treatment. In summary, blood vessel normalization could promote immune infiltration and repress cancer metastasis while immune cell infiltration can promote blood vessel normalization through a positive feedback loop.

Rapid one-pot isothermal amplification reassembled of fluorescent RNA aptamer for SARS-CoV-2 detection.

The outbreak of SARS-CoV-2 poses a serious threat to human life and health. A rapid nucleic acid tests can effectively curb the spread of the disease. With the advantages of fluorescent RNA aptamers, low background and high sensitivity. A variety of fluorescent RNA aptamer sensors have been developed for the detection of nucleic acid. Here, we report a hypersensitive detection platform in which SARS-CoV-2 initiates RTF-EXPAR to amplify trigger fragments. This activation leads to the reassembled of the SRB2 fluorescent RNA aptamer, restoring its secondary structure for SR-DN binding and turn-on fluorescence. The platform completes the assay in 30 min and all reactions occur in one tube. The detection limit is as low as 116 aM. Significantly, the platform's quantitative analyses were almost identical to qPCR results in simulated tests of positive samples. In conclusion, the platform is sensitive, accurate and provides a new protocol for point-of-care testing of viruses.

Catalpolaglycone disrupts mitochondrial thermogenesis by specifically binding to a conserved lysine residue of UCP2 on the proton leak tunnel.

BACKGROUND: Catalpol (CAT), a naturally occurring iridoid glycoside sourced from the root of Rehmannia glutinosa, affects mitochondrial metabolic functions. However, the mechanism of action of CAT against pyrexia and its plausible targets remain to be fully elucidated. PURPOSE: This study aimed to identify the specific targets of CAT for blocking mitochondrial thermogenesis and to unveil the unique biological mechanism of action of the orthogonal binding mode between the hemiacetal group and lysine residue on the target protein in vivo. METHODS: Lipopolysaccharide (LPS)/ carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced fever models were established to evaluate the potential antipyretic effects of CAT. An alkenyl-modified CAT probe was designed to identify and capture potential targets. Binding capacity was tested using in-gel imaging and a cellular thermal shift assay. The underlying antipyretic mechanisms were explored using biochemical and molecular biological methods. Catalpolaglycone (CA) was coupled with protein profile identification and molecular docking analysis to evaluate and identify its binding mode to UCP2. RESULTS: After deglycation of CAT in vivo, the hemiacetal group in CA covalently binds to Lys239 of UCP2 in the mitochondria of the liver via an ɛ-amine nucleophilic addition. This irreversible binding affects proton leakage and improves mitochondrial membrane potential and ADP/ATP transformation efficiency, leading to an antipyretic effect. CONCLUSION: Our findings highlight the potential role of CA in modulating UCP2 activity or function within the mitochondria and open new avenues for investigating the therapeutic effects of CA on mitochondrial homeostasis.

Tetrandrine inhibits aldosterone synthesis by covalently targeting CYP11A1 to attenuate hypertension.

Introduction: Tetrandrine (Tet) is the main pharmacological component of Stephania tetrandra S. Moore, which is a well-documented traditional Chinese medicine known for its diuretic and antihypertensive properties. Unraveling the specific targets and mechanisms of Tet involved in inducing diuresis and mitigating hypertension can provide valuable insights into its therapeutic effects. This study aimed to explore the diuretic and antihypertensive targets and mechanisms of Tet using chemical biology coupled with activity analyses in vivo and in vitro. Methods: The diuretic effects of Tet were evaluated using a water-loaded mouse model. The direct target proteins for the diuretic and antihypertensive effects of Tet were determined using chemical biology. Furthermore, the molecular mechanism of Tet binding to target proteins was analyzed using a multidisciplinary approach based on the structure and function of the proteins. Finally, the effects of the Tet-targeted protein on downstream signaling pathways and blood pressure were evaluated in hypertensive model rats. Results: Tet exhibited significant antihypertensive and potassium-preserving diuretic effects. The mechanism underlying these effects involves the modulation of the enzyme activity by covalent binding of Tet to Cys423 of CYP11A1. This interaction alters the stability of heme within CYP11A1, subsequently impeding electron transfer and inhibiting aldosterone biosynthesis. Discussion: This study not only revealed the mechanism of the diuretic and antihypertensive effects of Tet but also discovered a novel covalent inhibitor of CYP11A1. These findings contribute significantly to our understanding of the therapeutic potential of Tet and provide a foundation for future research in the development of targeted treatments for hypertension.

Thirdhand Smoke May Promote Lung Adenocarcinoma Development through HN1.

Thirdhand smoke (THS) refers to residual tobacco smoking pollutants that can be adsorbed to indoor surfaces and dust and persist for years after active smoking. THS-related chemicals such as N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are tobacco-specific lung carcinogens that involved in lung cancer development and progression. In this study, we computed the differentially expressed genes (DEGs) between THS and paired control samples. THS-related overexpressed genes (OEs) were overlapped with OEs of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Survival analyses of these overlapped genes were performed using LUAD and LUSC data. 6 genes were selected for validation based on their expression levels and prognostic value. Hematological and neurological expressed 1 (HN1) was further selected due to its novelty in LUAD research. The potential roles of HN1 in LUAD were explored in several ways. In summary, HN1 is overexpressed in THS samples and is associated with the prognosis of patients with LUAD. It may promote cancer progression through several pathways and could serve as a potential therapeutic target especially for THS-related LUAD. In-depth mechanistic studies and clinical trials are warranted.

Deep cortical microinfarction induced by femtosecond laser in mice: Long-term secondary pathological changes in corresponding superficial cortex.

BACKGROUND AND PURPOSE: Previous studies have explored the clinical consequences of cortical microinfarction, mainly age-related cognitive decline. However, functional impairment of deep cortical microinfarction remains poorly understood. Based on anatomical knowledge and previous research, we infer that damage to the deep cortex may lead to cognitive deficits and communication impairment between the superficial cortex and thalamus. This study aimed to develop a new model of deep cortical microinfarction based on femtosecond laser ablation of a perforating artery. METHODS: Twenty-eight mice were anesthetized with isoflurane, and a cranial window was thinned using a microdrill. Intensively focused femtosecond laser pulses were used to produce perforating arteriolar occlusions and ischemic brain damage was examined using histological analysis. RESULTS: Occlusion of different perforating arteries induced different types of cortical microinfarctions. Blocking the perforating artery, which enters the cerebral cortex vertically and has no branches within 300 µm below, can result in deep cortical microinfarction. Moreover, this model showed neuronal loss and microglial activation in the lesions as well as dysplasia of nerve fibers and ß-amyloid deposition in the corresponding superficial cortex. CONCLUSIONS: We present here a new model of deep cortical microinfarction in mice, in which specific perforating arteries are selectively occluded by a femtosecond laser, and we preliminarily observe several long-term effects related to cognition. This animal model is helpful in investigating the pathophysiology of deep cerebral microinfarction. However, further clinical and experimental studies are required to explore deep cortical microinfarctions in greater molecular and physiological detail.

Dual-bioactivity-based liquid chromatography-coupled quadrupole time-of-flight mass spectrometry for NF-κB inhibitors and ß2AR agonists identification in Chinese Medicinal Preparation Qingfei Xiaoyan Wan.

Traditional Chinese medicine (TCM) preparations have been used as an effective multitarget strategy for the treatment of complex diseases; however, their bioactive constituents are undefined and difficult to identify. In this study, a simple and dual-target method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with dual-bioactive (NF-κB and ß(2)-adrenergic receptor) luciferase reporter assay systems was developed for the rapid determination of various bioactive compounds of TCM preparations. Qingfei Xiaoyan Wan, a TCM preparation used for the clinical therapy of asthma, was analyzed with this method. Potential anti-inflammatory and spasmolytic constituents were screened using NF-κB and ß(2)-adrenergic receptor activity luciferase reporter assay systems and simultaneously identified according to the time-of-flight mass spectrometry data. One ß(2)-adrenergic receptor agonist (ephedrine) and four structural types of NF-κB inhibitors (arctigenin derivatives, cholic acid derivatives, chlorogenic acid, and sinapic acid) were characterized. Tracheloside was considered a new NF-κB inhibitor. Further cytokine and chemokine detection confirmed the anti-inflammatory effects of the potential NF-κB inhibitors. The integration of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry and dual-bioactive human cell functional evaluation systems proved to be a simple and effective strategy for the rapid screening of various bioactive compounds in TCM preparations used to treat complex diseases.

Carboxymethylcellulose sodium improves the pharmacodynamics of 1-deoxynojirimycin by changing its absorption characteristics and pharmacokinetics in rats.

1-Deoxynojirimycin (DNJ) has excellent inhibitory activity against alpha-glucosidase and can therefore decrease the postprandial blood glucose level in humans. However, a major limitation of DNJ is its fast absorption rate compared with other alpha-glucosidase inhibitors. In this study, we investigated the effect of adjuvants on the pharmacokinetics of DNJ, and found that carboxymethylcellulose sodium (CMCNa) can remarkably improve the activity of DNJ on glucose levels. When DNJ was used in combination with CMCNa, its absorption was suppressed and delayed by CMCNa. CMCNa can also change the pharmacokinetics of DNJ in rats. Pharmacodynamics were further studied using the oral glucose tolerance test, and the results confirmed that CMCNa can enhance DNJ's modulation of glucose level. All the results indicate that carboxymethylcellulose sodium can improve the pharmacodynamics of 1-deoxynojirimycin by changing the absorption characteristics and pharmacokinetics of DNJ in rats.

Ursolic acid alleviates tetrandrine-induced hepatotoxicity by competitively binding to the substrate-binding site of glutathione S-transferases.

BACKGROUND: Tetrandrine (TET), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, is the only approved medicine in China for silicosis. However, TET-induced hepatotoxicity has raised safety concerns. The underlying toxic targets and mechanism induced by TET remain unclear; there are no targeted detoxification strategies developed for TET-induced hepatotoxicity. Ursolic acid (UA), a pentacyclic triterpene with liver protective effects, may have detoxification effects on TET-induced hepatotoxicity. PURPOSE: This study aims to explore toxic targets and mechanism of TET and present UA as a potential targeted therapy for alleviating TET-induced hepatotoxicity. METHODS: A TET-induced liver-injury model was established to evaluate TET toxicity and the potential UA detoxification effect. Alkenyl-modified TET and UA probes were designed to identify potential liver targets. Pharmacological and molecular biology methods were used to explore the underlying toxicity/detoxification mechanism. RESULTS: TET induced liver injury by covalently binding to the substrate-binding pocket (H-site) of glutathione S-transferases (GSTs) and inhibiting GST activity. The covalent binding led to toxic metabolite accumulation and caused redox imbalance and liver injury. UA protected the liver from TET-induced damage by competitively binding to the GST H-site. CONCLUSION: The mechanism of TET-induced hepatotoxicity is related to irreversible binding with the GST H-site and GST-activity inhibition. UA, a natural antidote, competed with TET on H-site binding and reversed the redox imbalance. This study revealed the hepatotoxic mechanism of TET and provided a targeted detoxifying agent, UA, to alleviate hepatotoxicity caused by GST inhibition.

Flexible and easy-handling pristine polypyrrole membranes with bayberry-like vesicle structure for enhanced Cr(VI) removal from aqueous solution.

Polypyrrole has been extensively explored for Cr(VI) removal from wastewater towing to the advantages of superior performance, low cost, facile synthesis, and high environmental stability. However, the unsatisfactory adsorption capacity and complicated process of adsorbent separation from aqueous solutions remain a huge challenge, limiting its practical application. Herein, a flexible PPy membrane with bayberry-like vesicle structures (PPy-B) was prepared via template-assisted interfacial polymerization. It was found that sodium sulfosalicylate not only improved the flexibility and strength of the PPy-B membrane for easy-handling but also participated in the polymerization of PPy as a dopant to improve the specific surface area and doping level for increasing adsorption sites. Benefiting from these, the easy-handling PPy-B membrane exhibited a high adsorption capacity (586.90-682.50 mg/g at 298-318 K), a high reusability (five adsorption-desorption cycles), and a high ultimate adsorption capacity after adsorption-desorption cycles until membrane failure (1174.86 mg/g at 298 K). The proposed mechanisms of the enhanced Cr(VI) removal involve electrostatic adsorption, reduction, and ion exchange. This flexible PPy membrane therefore shows attractive advantages in wastewater treatment.

Silylium ion-mediated cage-opening functionalization of closo-B10H102- salts.

The cage-opening functionalization of stable closo-B10H102- salts is a great way to get various boron clusters. However, the known methods to mediate cage-opening functionalization rely on the use of strong acids, which suffer from low efficiency and narrow substrate scope. Herein, an efficient method to synthesize 6-substituted decaboranyl ethers and sulfides has been developed. The reaction was mediated by trimethylsilyl trifluoromethanesulfonate (TMSOTf) and occurred at room temperature. Six 6-substituted ethers were obtained in 65-92% yields and five 6-substituted sulfides were prepared in 38-58% yields. The reaction had excellent regioselectivity, affording the single B(6) regioisomer in all cases. The interaction between the B-H bonds of the boron cage and the silylium ion was believed to be the key factor in the reaction.

CCR5 is a prognostic biomarker and an immune regulator for triple negative breast cancer.

This study aims to explore the clinical implications and potential mechanistic functions of CCR5 in triple negative breast cancer. Briefly, we demonstrated that CCR5 is overexpressed in TNBC and is associated with better prognosis of TNBC. CCR5 expression is positively correlated with tumor immune cell infiltration and tumor immune response related pathways. Multi-omics data analyses identified CCR5 associated genomic and proteomic changes. CCR5 overexpression was associated with better overall survival in TNBC patients with TP53 mutation. We also summarized the latest findings on ICB efficacy related genes and explored the association between CCR5 and those genes. These results indicated that CCR5 is a potential tumor suppressor gene and individualized therapeutic strategy could be established based on multi-omics background and expression pattern of ICB related genes. In conclusion, CCR5 is associated with better survival of TNBC patients with TP53 mutation, which may exert its roles through tumor immune environment.

Silencing c-Myc Enhances the Antitumor Activity of Bufalin by Suppressing the HIF-1α/SDF-1/CXCR4 Pathway in Pancreatic Cancer Cells.

BACKGROUND: Pancreatic cancer is one of the most aggressive malignancies. Bufalin, a traditional Chinese medicine, has been used to treat pancreatic cancer as an antitumor agent although the mechanism by which it exerts its effects is still unclear. c-Myc has been found to be overexpressed in more than half of human cancers including pancreatic cancer. However, the role of c-Myc in pancreatic cancer cells and its influence in bufalin-treated pancreatic cancer are yet to be clarified. The present study aimed to investigate the role of c-Myc in the antitumor activity of bufalin in pancreatic cancer. METHODS: c-Myc siRNA and overexpression plasmid were transfected into pancreatic cancer cells to construct the cell models. c-Myc expression was detected via quantitative real-time polymerase chain reaction and western blot. The effect of c-Myc on bufalin-induced inhibition of cell proliferation was detected via CCK-8 assay. Cell apoptosis and the cell cycle were analyzed via flow cytometry. Cell invasion and migration was detected via Transwell and wound healing assays, respectively. In addition, the effect of bufalin on the suppression of tumor growth in vivo was studied in nude mice model subcutaneously injected with PANC-1 and SW1990 cells. Hematoxylin-eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay were used to evaluate pathological changes in vivo. The expression of HIF-1α/SDF-1/CXCR4 were detected via western blot. RESULTS: CCK-8 assay showed that bufalin could inhibit the proliferation of pancreatic cancer cell, and c-Myc downregulation enhanced this effect. Similarly, c-Myc downregulation enhanced the effect of bufalin on cell cycle arrest, apoptosis, and the invasion and migration of pancreatic cancer cell in vitro. Further mechanism assay showed that c-Myc enhances the effect by regulating the HIF-1α/SDF-1/CXCR4 signaling pathway. The in vivo studies verified the results that c-Myc enhances the effect of bufalin through regulation of the HIF-1α/SDF-1/CXCR4 pathway. CONCLUSIONS: Downregulation of c-Myc enhanced the antitumor activity of bufalin in pancreatic cancer cells by suppressing the HIF-1α/SDF-1/CXCR4 pathway. These findings indicate that c-Myc inhibitors could enhance the clinical therapeutic effect of bufalin and may expand the clinical application of bufalin accordingly.

Silencing RRM2 inhibits multiple myeloma by targeting the Wnt/ß­catenin signaling pathway.

Ribonucleotide reductase M2 (RRM2) is one of the two subunits that comprise ribonucleotide reductase (RR), the enzyme that catalyzes the conversion of ribonucleotide 5'­diphosphates into 2'­deoxyribonucleotides, which are required for DNA synthesis. RRM2 is a stress response factor important for the development of several tumors. However, its role in multiple myeloma (MM) remains to be fully elucidated. The present study aimed to investigate the role of RRM2 in MM. The expression of RRM2 in patients with MM was analyzed using the Oncomine database. The results demonstrated that RRM2 expression was higher in MM compared with healthy subjects. Reverse transcription­quantitative polymerase chain reaction and western blot results revealed that RRM2 expression was decreased following transfection with a small interfering RNA targeting RRM2 into NCI­H929 cells. RR activity and Cell Counting Kit­8 assays demonstrated that RRM2 silencing reduced RR activity and inhibited cell proliferation. Annexin V­propidium iodide staining indicated that the percentage of apoptotic NCI­H929 cells was increased following RRM2 silencing compared with that in the control group. Increased phosphorylation of H2AX indicated that RRM2 silencing may activate the DNA­damage response pathway in NCI­H929 cells. Western blot analysis revealed that protein levels of the apoptosis­associated factor Bcl­2 were reduced, whereas Bax, cleaved caspase­3 and cleaved poly(ADP­ribose) polymerase 1 were upregulated following RRM2 silencing compared with the control group. In addition, the results demonstrated that RRM2 silencing may inhibit target gene expression in the Wnt/ß­catenin signaling pathway by increasing the phosphorylation of glucose synthase kinase 3ß. These findings indicated that RRM2 may be involved in the proliferation and apoptosis of MM cells via the Wnt/ß­catenin signaling pathway, suggesting that RRM2 may represent a novel therapeutic target for MM.

Synergistic suppression effect on tumor growth of acute myeloid leukemia by combining cytarabine with an engineered oncolytic vaccinia virus.

BACKGROUND: In consideration of the drug resistance and side effects associated with cytarabine, one of the most effective drugs for the treatment of acute myeloid leukemia (AML), there is a need for safer and effective strategies. METHODS: In the present investigation, we fabricated a new oncolytic vaccinia virus (oVV-ING4), which expresses the inhibitor of growth family member 4 (ING4) and explored its antitumor activity individually and in combination with cytarabine in AML cells. RESULTS: The experiments confirmed that oVV can efficiently and specifically infect leukemia cells, and augment the ING4 gene expression. Flow cytometry and western blot demonstrated that oVV-ING4 enhances apoptosis and G2/M phase arrest in AML cells, and causes remarkable cancer cell death. In addition, the synergistic efficiency of oVV-ING4 and cytarabine was investigated in vitro and in vivo; the combination significantly inhibited the survival of leukemia cells in vitro and xenografted KG-1 AML tumor growth in vivo. CONCLUSION: In brief, oVV-ING4 can increase the sensitivity of leukemia cells to cytarabine and induce cell apoptosis in vitro and in vivo. Thus, oVV-ING4 may be a promising therapeutic candidate for leukemia and in combination with cytarabine represents a potential antitumor therapy.