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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

The small-molecule IAP antagonist AT406 inhibits pancreatic cancer cells in vitro and in vivo

In the present study, we tested the anti-pancreatic cancer activity by AT406, a small-molecule antagonist of IAP (inhibitor of apoptosis proteins). In established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells, treatment of AT406 significantly inhibited cell survival and proliferation. Yet, same AT406 treatment was non-cytotoxic to pancreatic epithelial HPDE6c7 cells. AT406 increased caspase-3/-9 activity and provoked apoptosis in the pancreatic cancer cells. Reversely, AT406′ cytotoxicity in these cells was largely attenuated with pre-treatment of caspase inhibitors. AT406 treatment caused degradation of IAP family proteins (cIAP1 and XIAP) and release of cytochrome C, leaving Bcl-2 unaffected in pancreatic cancer cells. Bcl-2 inhibition (by ABT-737) or shRNA knockdown dramatically sensitized Panc-1 cells to AT406. In vivo, oral administration of AT406 at well-tolerated doses downregulated IAPs (cIAP1/XIAP) and inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) nude mice. Together, our preclinical results suggest that AT406 could be further evaluated as a promising anti-pancreatic cancer agent. - Highlights: • AT406 is cytotoxic to established/primary human pancreatic cancer cells. • AT406 provokes caspase-dependent apoptosis in pancreatic cancer cells. • AT406 causes degradation of key IAPs and promotes cytochrome C release. • Bcl-2 inhibition or knockdown dramatically sensitizes Panc-1 cells to AT406. • Oral administration of AT406 inhibits Panc-1 tumor growth in SCID nude mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

AZD5153, a novel BRD4 inhibitor, suppresses human thyroid carcinoma cell growth in vitro and in vivo

Highlights: • AZD5153 inhibits thyroid carcinoma cell survival, proliferation and cell cycle progression. • AZD5153 induces apoptosis activation in human thyroid carcinoma cells. • BRD4 is over-expressed in human thyroid carcinoma cells. • AZD5153 downregulates c-Myc, Bcl-2 and cyclin D1 in human thyroid carcinoma cells. • AZD5153 oral administration inhibits TPC-1 xenograft growth in SCID mice. The development of novel anti-papillary thyroid carcinoma agents is urgent. AZD5153 is a novel and specific Bromodomain-containing protein 4 (BRD4) inhibitor. Here, we show that AZD5153 dose-dependently inhibited survival, proliferation and cell cycle progression in TPC-1 cells and primary human thyroid carcinoma cells. Yet, it was non-cytotoxic to the primary thyroid epithelial cells. AZD5153 induced caspase-3/-9 and apoptosis activation in TPC-1 cells and primary cancer cells. Its cytotoxicity in TPC-1 cells was significantly attenuated with co-treatment of the caspase inhibitors. BRD4 expression was elevated in TPC-1 and primary human thyroid carcinoma cells, but was low in the thyroid epithelial cells. BRD4-regulated proteins, including c-Myc, Bcl-2 and cyclin D1, were significantly downregulated following AZD5153 treatment in TPC-1 and primary cancer cells. In vivo, oral administration of AZD5153 at well-tolerated doses significantly inhibited TPC-1 xenograft growth in severe combined immunodeficient (SCID) mice. BRD4-dependent proteins, Myc, Bcl-2 and cyclin D1, were also downregulated in AZD5153-treated tumor tissues. Collectively, the results suggest that targeting BRD4 by AZD5153 inhibits human thyroid carcinoma cell growth in vitro and in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dihydroartemisinin potentiates antitumor activity of 5-fluorouracil against a resistant colorectal cancer cell line

Although the combination of chemotherapy and surgical resection has effectively increased the survival rate of colorectal cancer patients in recent decades, acquired drug resistance is still a problem that leads to treatment failure. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has recently been reported to show anticancer effects against numerous types of cancer, including colorectal cancer. This study showed that DHA exerted a strong anticancer effect against several colorectal cancer cell lines. We also found that p53 knockout colorectal cancer HCT116 cells (HCT116 TP53{sup −/−}) were not sensitive to 5-fluorouracil (5-FU) treatment, unlike wild-type HCT116 cells. Interestingly, co-treatment with DHA could effectively restore the anticancer effect of 5-FU against HCT116 TP53{sup −/−} cells, which manifested as the inhibition of proliferation and induction of reactive oxygen species (ROS)-mediated apoptosis and was accompanied by the upregulation of B-cell lymphoma 2 (BCL-2) and downregulation of the BCL-2-associated X protein (BAX). These findings suggested that DHA could effectively sensitize cells to 5-FU through ROS-mediated apoptosis and the alteration of the BCL-2/BAX expression ratio, which indicated that this may be one of the mechanisms of the DHA-promoted 5-FU anticancer effect.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Protection from Cr(VI)-induced malignant cell transformation and tumorigenesis of Cr(VI)-transformed cells by luteolin through Nrf2 signaling

Cr(VI) is a well known environmental carcinogen, but its mechanism of action and the measures required to mitigate its effects remain to be investigated. Our previous studies showed that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) caused malignant transformation, that these transformed cells progressed through tumorigenesis, and that luteolin, a natural compound, inhibited both of these processes. The present study investigates the underlying mechanisms by which luteolin protects cells against Cr(VI)-induced transformation and tumorigenesis. The present study shows that luteolin activates inducible Nrf2 to inhibit Cr(VI)-generated reactive oxygen species (ROS) in normal BEAS-2B cells. The decreased ROS level is likely responsible for the protective effect of luteolin against Cr(VI)-induced malignant cell transformation in normal cells. By contrast, in cells that have been transformed by Cr(VI), Nrf2 is constitutively activated, and its target proteins, heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and superoxide dismutase 1/2 (SOD1/SOD2) are all constitutively activated, and ROS levels are low. Bcl-2, an anti-apoptotic protein and target protein of Nrf2 is elevated. Cr(VI)-transformed BEAS-2B cells develop apoptosis resistance, increasing the survival of these transformed cells. Luteolin decreases interactions between Nrf2 and the antioxidant response element sites of its target anti-apoptotic and antioxidant proteins, Bcl-2, Bcl-XL, and HO-1, which results in decreased constitutive Nrf2 activation. The decreased constitutive Nrf2 activation, decrease in Nrf2 target proteins and consequent apoptosis resistance by luteolin are possible mechanisms that mediate the protective effect of luteolin in Cr(VI)-transformed cells. - Highlights: • Constitutive Nrf2 activation in Cr(VI)-transformed cells is oncogenic. • Constitutive Nrf2 activation decreases ROS with development of apoptosis resistance. • Luteolin inhibits constitutive Nrf2 activation in Cr(VI)-transformed cell. • Dietary strategies using luteolin may prevent Cr(VI)-induced carcinogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Deregulation of Nrf2/ARE signaling pathway causes susceptibility of dystrophin-deficient myotubes to menadione-induced oxidative stress

Highlights: • Dystrophin knock-down myotubes are more vulnerable to oxidative stress than control myotubes. • Activation of Nrf2 is impaired in dystrophin knock-down myotubes. • Akt signaling is responsible for Nrf2 translocation into the nucleus. • Bcl-2 expression is regulated by nuclear Nrf2. • Sulforaphane can prevent the damage of dystrophin knock-down myotubes under menadione-induced oxidative stress. Duchenne muscular dystrophy (DMD) is an X chromosome-linked disorder caused by a mutation in the dystrophin gene. Many previous studies reported that the skeletal muscles of DMD patients were more susceptible to oxidative stress than those of healthy people. However, not much has been known about the responsible mechanism of the differential susceptibility. In this study, we established dystrophin knock-down (DysKD) cell lines by transfection of dystrophin shRNA lentiviral particles into C2 cells and found that DysKD myotubes are more vulnerable to menadione-induced oxidative stress than control myotubes. We focused on the nuclear erythroid 2-related factor 2 (Nrf2) which is a transcription factor that regulates the expression of phase II antioxidant enzymes by binding to the antioxidant response element (ARE). Under menadione-induced oxidative stress, the translocation of Nrf2 to the nucleus is significantly decreased in the DysKD myotubes. In addition, the binding of Nrf2 to ARE site of Bcl-2 gene as well as protein expression of Bcl-2 is decreased compared to the control cells. Interestingly, sulforaphane increased Akt activation and Nrf2 translocation to the nucleus in the DysKD myotubes. These results suggest that the Nrf2 pathway might be the responsible pathway to the oxidative stress-induced muscle damage in DMD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo

Highlights: • B16-exosomes induced the apoptosis of CD4{sup +} T cells. • B16-exosomes promoted the tumor growth by eliminating T cells in the tumor. • B16-exosomes could enter CD4{sup +} T cells and activate caspase family proteins. • MicroRNAs in exosomes may target anti-apoptotic proteins, such as BCL-2. Tumor-derived exosomes (TEX) play an important role in the escape of tumor cells from immune surveillance. However, the details of the mechanism are not fully understood. In this study, the apoptosis of CD4{sup +} T cells increased during treatment with B16-derived exosomes in vitro and in vivo, resulting in accelerated growth of melanoma cells in mice. While the release of exosomes was blocked by disrupting the expression of Rab27a, tumor growth was clearly inhibited, and the percentage of T cells in the tumor environment increased. At the same time, Western blot showed that TEX could increase the activation of caspase-3, caspase-7 and caspase-9 but not caspase-8, down-regulating the anti-apoptotic proteins, including BCL-2, MCL-1 and BCL-xL in CD4{sup +} T cells, and indicating that the TEX activates the mitochondrial apoptotic pathway of CD4{sup +} T cells. These reductions were probably associated with the release of microRNAs, such as miR-690, from TEX to T cells. Our present study reveals for the first time that melanoma-released exosomes may directly activate the mitochondrial apoptotic pathway of CD4{sup +} T cells through their microRNA cargo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Sodium Superionic Conductors Based on Clusters

Owing to the high abundance and low cost of sodium (Na), Na-based rechargeable batteries hold great potential for large-scale applications in the future energy industry. However, as key component of the battery electrolyte, only a few Na-based superionic conductors can reach the ionic conductivity comparable to that of liquid or gel electrolytes. Here, we provide a guideline for the development of cluster-based Na-rich antiperovskite superionic conductors using computational studies. With a selected cluster ion BCl 4 – , we are able to achieve high-room-temperature Na-ionic conductivity over 10 –3 S/cm and low activation energies below 0.2 eV in the antiperovskite crystals Na 3 S(BCl 4 ) and Na 3 S(BCl 4 ) 0.5 I 0.5 . In addition, these materials have large bandgaps and favorable mechanical properties. Here, a comprehensive study of the stability and formation energy of these materials further illustrates possible routes for their synthesis. New insights into the conduction mechanism of these cluster-based superionic conductors are provided, including the cooperative motion of Na ions and the significant reduction of the migration barrier due to the changing orientation of the cluster ion.

25 ENERGY STORAGE↗
DOE OSTI2017

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors

Mcl-1 is a pro-apoptotic BH 3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 µM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the residue that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl2 at only 5 µM and Bcl-xL at >99 µM, and induce cleaved caspase 3 in MV4-11 cells with an IC 50 of 3 µM after 6 hours

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Spectral decomposition of human BCL2 bonded to a PROTAC

In this study, we have decomposed the linear infrared spectra and two-dimensional infrared spectroscopy of a VHL-recruiting Proteolysis-targeting chimera (PROTAC) complex with BCL-2 to understand the spectral signatures of this complex. Our findings show that both VHL and BCL-2 units have distinct spectral signatures that contribute to the total spectra in different regions. Furthermore, we observed that the interaction between VHL and BCL-2 within the PROTAC complex leads to unique spectral features, indicating a strong synergistic effect. Through detailed analysis, specific bands were identified that correspond to the vibrational modes of the individual components, as well as their interactive modes within the complex. This study provides valuable insight into the molecular interactions within the PROTAC complex, offering a deeper understanding of its structure and function. These insights could be pivotal in designing more efficient PROTACs for targeted protein degradation in therapeutic applications.

Nauta, Wiestke [University of Groningen]↗
DOE OSTI2017

Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2008

Radio-sensitization of Prostate Cancer Cells by Monensin Treatment and its associated Gene Expression Profiling Changes

Radio-resistant or recurrent prostate cancer represents a serious health risk for approximately 20%-30% of patients treated with primary radiation therapy for clinically localized prostate cancer. Here, we investigated the effect of monensin on sensitizing radiation mediated cell killing of two radio-resistant prostate cell lines Lncap (P53+ and AR+) and PC3 (P53- and AR-). Treatment with monensin alone (5 micromoles-20 micromoles) showed a significant direct cell killing of Lncap (10-30%), but not PC3 cells. Monensin was also shown to successfully sensitize Lncap cells to X-ray radiation (2Gy-10Gy) mediated cell death, up to 50% of killing with the combined treatment. To better understand the mechanisms of radio-resistance of these two cell lines and their different response to monensin, the apoptosis related gene expression profiles in both cell lines were analyzed using cDNA PCR array. Without any treatment, PC3 showed a much higher expression level of antiapoptosis genes than Lncap in the BCL2 family, the caspase/card family and the TNF ligand/receptor family. At 2 hr after 20 micormolar monensin treatment alone, only the TRAF and CIDE family showed a greater induction in Lncap cells than in PC3. Exposures to 10 Gy X-rays alone of Lncap cells significantly induced gene expression levels in the death and death receptor domain family, the TNF ligand and receptor family, and apoptotic group of BCL2 family; whereas exposures of PC3 induced only the expression of genes in the anti-apoptosis group of CASP and CARD family. Furthermore, we selectively suppressed the expression of several anti-apoptosis genes (BCL-xl, Bcl2A1, BIRC2, BIRC3 and CASP2) in PC3 cells by using the siRNA treatment. Exposure to 10Gy X-rays alone showed an enhanced cell killing (about 15%) in BCL-x1 silenced cells, but not in cells with siRNA treatment targeting other anti-apoptosis genes. We also exposed PC3 cells to protons in the Bragg peak region to compare the effectiveness of cell killing of X-rays. Interestingly, in comparison to X-rays, protons significantly reduced the gene expression in the anti-apoptosis family, suggesting that proton treatment may be more effective for PC3 cells. As a conclusion, monensin was found to sensitize Lncap cells, but not PC3, and over-expression of Bcl-xl cells may be responsible for the radio- or chemo-resistance characteristics of PC3 cells.

Zhang Ye↗
DOE OSTI2025

A Route to Design Novel Functional Peptides by Applying a Denoising Diffusional Model to mRNA Display Libraries

In vitro directed evolution techniques, such as mRNA display, enable peptide ligand discovery and optimization. However, physical libraries that rely on a genetic code can only search a small fraction of sequence space due to inherent biases in the genetic code and experimental limitations. To address this challenge, denoising diffusion implicit models (DDIMs) are applied to generate novel peptide ligands against B‐cell lymphoma extra‐large (Bcl‐x L ), a key cancer target. Starting with high‐throughput sequencing data from previous selections, a DDIM is trained to produce novel sequences with high affinity binding. Experimental validation confirms that most generated sequences are functionally equivalent to the original library members for Bcl‐x L binding and demonstrated comparable binding kinetics and affinity relative to the wildtype and nearest original neighbors. Importantly, this approach generated rare sequences not easily accessible via mutation and directed evolution. These results indicate that DDIMs can complement and expand directed evolution data, efficiently exploring underrepresented regions of sequence space. This approach provides a broadly applicable framework for accelerating ligand discovery and optimizing molecular properties across diverse targets.

Qi, Pearl [Mork Family Department of Chemical Engi↗
DOE OSTI2019

Cyanohydridoborate Anions: Synthesis, Salts, and Low‐Viscosity Ionic Liquids

Abstract High‐yield syntheses up to molar scales for salts of [BH(CN) 3 ] − ( 2 ) and [BH 2 (CN) 2 ] − ( 3 ) starting from commercially available Na[BH 4 ] (Na 5 ), Na[BH 3 (CN)] (Na 4 ), BCl 3 , (CH 3 ) 3 SiCN, and KCN were developed. Direct conversion of Na 5 into K 2 was accomplished with (CH 3 ) 3 SiCN and (CH 3 ) 3 SiCl as a catalyst in an autoclave. Alternatively, Na 5 is converted into Na[BH{OC(O) R } 3 ] ( R =alkyl) that is more reactive towards (CH 3 ) 3 SiCN and thus provides an easy access to salts of 2 . Some reaction intermediates were identified, for example, Na[BH(CN){OC(O)Et} 2 ] (Na 7 b ) and Na[BH(CN) 2 {OC(O)Et}] (Na 8 b ). A third entry to 2 and 3 uses ether adducts of BHCl 2 or BH 2 Cl such as the commercial 1,4‐dioxane adducts that react with KCN and (CH 3 ) 3 SiCN. Alkali metal salts of 2 and 3 are convenient starting materials for organic salts, especially for low viscosity ionic liquids (ILs). [EMIm] 3 has the lowest viscosity and highest conductivity with 10.2 mPa s and 32.6 mS cm −1 at 20 °C known for non‐protic ILs. The ILs are thermally, chemically, and electrochemically robust. These properties are crucial for applications in electrochemical devices, for example, dye‐sensitized solar cells (Grätzel cells).

Bischoff, Lisa A.↗
DOE OSTI2019

Mechanistic studies of the apoptosis induced by the macrocyclic natural product tetrandrine in MGC 803 cells

Tetrandrine (Tet) is a macrocyclic tetrahydroisoquinoline alkaloid isolated from Stephania tetrandra S. Moore along with other Chinese and Japanese herbs. It has been used extensively for the treatment of silicosis, autoimmune disorders, inflammatory diseases and cardiovascular diseases. Of late, Tet has garnered increasing attention for its anticancer activity and its efficacy to reverse chemoresistance. In this study, we evaluated the cytotoxicity of Tet on MGC 803 gastric cancer cells using the methyl thiazolyl tetrazolium (MTT) assay. In addition, apoptosis and cell cycle were analyzed through flow cytometry, mitochondrial membrane potential (MMP) was measured using fluorescence microscopy and migration of cells was determined by transwell assay. It was observed that Tet efficiently inhibited the proliferation of MGC 803 cells in a concentration-dependent and time-dependent manner and reduced the number of colonies at low concentrations. It induced apoptosis through mitochondrial dysfunction, which may be related with upregulated Bcl-2-associated X protein (Bax), and downregulated of B cell lymphoma 2 (Bcl-2). On the other hand, Tet blocked the cell cycle at Gap 2 (G2)/mitosis (M) phase, which was associated with the upregulation of p21{sup CIP1/WAF1}. Furthermore, Tet elevated the intracellular reactive oxygen species (ROS) level and suppressed the migration of MGC 803 cells. Altogether, we demonstrated that Tet inhibited the proliferation and migration of gastric cancer MGC 803 cells and thus might be a potential drug candidate for the treatment of gastric cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Caffeine enhances the anti-tumor effect of 5-fluorouracil via increasing the production of reactive oxygen species in hepatocellular carcinoma

The development of drug resistance affecting the prognosis of patients with hepatocellular carcinoma (HCC) leads to low survival rate of HCC patients. Caffeine is reported to have a function of protecting the liver and anti-tumor activity. Therefore, caffeine may be an ideal enhancer for HCC chemotherapy regimens. Our study showed that the combination of caffeine and 5-FU significantly inhibited the proliferation of HCC cells in vivo and in vitro comparing with caffeine or 5-FU monotherapy. The CI values of caffeine (0.5 mM) combined with 5-FU (25, 50 μM) were all less than 1, confirming that the utilization of drug combination has a synergistic inhibitory effect on the proliferation of HCC cells. Meanwhile, results of Western blot and TUNEL assays demonstrated that the apoptotic level of HCC cells in the combined group was significantly increased. The protein expression level of cleaved PARP was up-regulated, while the protein level of Bcl-2 and Bcl-xL was down-regulated. In addition, we found that ROS levels were increased in the 1 mM caffeine and 25 μM 5-FU combination group comparing with the control or single drug group. Taken together, this is the first study to demonstrate that the combination of caffeine and 5-FU inhibits HCC cells proliferation and promotes cellular apoptosis by regulating intracellular ROS production. The present data provides a basis for the application of caffeine combined with 5-FU as a novel chemotherapy regimen for HCC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Long non-coding RNA ANRIL is up-regulated in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic pathway

Antisense non-coding RNA in the INK4 locus (ANRIL) is a member of long non-coding RNAs and has been reported to be dysregulated in several human cancers. However, the role of ANRIL in bladder cancer remains unclear. This present study aimed to investigate whether and how ANRIL involved in bladder cancer. Our results showed up-regulation of ANRIL in bladder cancer tissues versus the corresponding adjacent non-tumor tissues. To explore the specific mechanisms, ANRIL was silenced by small interfering RNA or short hairpin RNA transfection in human bladder cancer T24 and EJ cells. Knockdown of ANRIL repressed cell proliferation and increased cell apoptosis, along with decreased expression of Bcl-2 and increased expressions of Bax, cytoplasmic cytochrome c and Smac and cleaved caspase-9, caspase-3 and PARP. However, no change of cleaved caspase-8 level was observed. Furthermore, in vivo experiment confirmed that knockdown of ANRIL inhibited tumorigenic ability of EJ cells in nude mice. Meanwhile, in accordance with in vitro study, knockdown of ANRIL inhibited expression of Bcl-2 and up-regulated expressions of Bax and cleaved caspase-9, but did not affect cleaved caspase-8 level. In conclusion, we first report that ANRIL possibly serves as an oncogene in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic apoptosis pathway. - Highlights: • We first report the role of ANRIL in bladder cancer. • ANRIL is obviously up-regulated in bladder cancer tissues. • ANRIL regulates bladder cancer cell proliferation and cell apoptosis through the intrinsic pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors

SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies. - Highlights: • Depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors. • Overexpression of SRC-3 enhanced cancer cell resistance to HDAC inhibitors. • SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. • Bufalin synergized with HDAC inhibitor attenuated AKT activation and reduced Bcl-2 levels in human cancer cell.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Synthetic peptide, Ala-Arg-Glu-Gly-Glu-Met, abolishes pro-proliferative and anti-apoptotic effects of high glucose in vascular smooth muscle cells

Apoptosis plays a critical role in normal vascular development and atherosclerosis. However, high glucose has been reported to generate a certain level of ROS that can inhibit vascular smooth muscle cell (VSMC) apoptosis, with the underlying mechanism remaining unclear. In this study, a synthetic peptide AREGEM (Ala-Arg-Glu-Gly-Glu-Met) exhibited antioxidative effects and was used to investigate its function in VSMCs during hyperglycaemia. MTT assay results demonstrated that AREGEM significantly attenuated high glucose-induced VSMCs proliferation. Flow cytometry displayed that high glucose levels inhibited cell apoptosis, whereas this effect was attenuated by pre-incubation with AREGEM. In addition, the 2′,7'-dichlorofluorescein diacetate (DCFH-DA) fluorescent probe assay further demonstrated that AREGEM reduced intracellular ROS accumulation in VSMCs. Furthermore, this peptide was able to prevent the decrease of caspase-3 activity and the increase of the ratio of Bcl-2/Bax protein in VSMCs exposed to high glucose. These findings demonstrated that AREGEM is able to abolish the effects of high glucose in VSMCs; therefore, this peptide can be a potential candidate to develop a novel strategy for curing diabetic related diseases. - Highlights: • A peptide, AREGEM, can reduce intracellular ROS accumulation in vascular smooth muscle cells (VSMCs). • AREGEM significantly inhibits high glucose-induced proliferation of VSMCs. • AREGEM attenuates the inhibitory effect of high glucose on VSMC Apoptosis and caspase-3 activity. • AREGEM decreases the ratio of Bcl-2/Bax protein in VSMCs exposed to high glucose.

60 APPLIED LIFE SCIENCES↗