Induction Of Apoptosis In Cancer Cells Research Articles

Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199.

Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro, a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition.

Concentration-Dependent Decitabine Effects on Primary NK Cells Viability, Phenotype, and Function in the Absence of Obvious NK Cells Proliferation-Original Article.

Acute myeloid leukemia (AML) cells can evade innate immune killing by modulating natural killer (NK) cells receptors and their cognate ligands in tumor cells, thus it may be possible to restore proper expression of immune receptors or ligands with immune sensitive drugs. Decitabine, as a hypomethylation agent, was approved for the treatment of AML and myelodysplastic syndrome. While clinical responses were contributed by epigenetic effects and the induction of cancer cell apoptosis, decitabine also has immune-mediated anti-tumor effects. After exposure to various concentration of decitabine for 24 h, the primary NK cells (AML-NK cells) cytotoxicity and receptor expression (NKG2D and NKp46) displayed parabola-shaped response, while U-shaped response was seen in cytokine release (IFN-γ and IL-10), and these effects were regulated by ERK and STAT3 phosphorylation level. Furthermore, AML-NK cells function displayed different response when the competitive MEK and STAT3 inhibitors applied respectively. Thus, we could conclude that the different dose of decitabine makes various effects on AML-NK cells function and receptors expression.

Anticancer therapeutic efficacy of biogenic Am-ZnO nanoparticles on 2D and 3D tumor models

The present study fabricates biogenic zinc oxide nanoparticles (ZnO NPs) with the aqueous leaf extract of Annona muricata (Am) plant collected from semi-evergreen forests of Odisha, India. The synthesized Am-ZnO NPs were physicochemically characterized. The ultraviolet/visible spectrum showed the maximum optical absorbance of Am-ZnO NPs at 355 nm. High-resolution transmission electron microscopy analysis presented the nearly spherical shape of Am-ZnO NPs with an average particle size of 80 nm. The net surface charge and hydrodynamic size of Am-ZnO NPs were measured to be ∼−2.59 mV and ∼417 nm, respectively. Am-ZnO NPs were found to be biocompatible and hemocompatible nature. Furthermore, Am-ZnO NPs displayed strong anticancer effects on both 2D and 3D tumor models. We observed a dose-dependent toxicity on both A549 and MOLT4 cells and observed a size reduction in the A549 tumor spheroids. Subsequently, we observed a depolarization in mitochondrial membrane potential of Am-ZnO NP–treated cancer cells leading to the apoptosis induction in cancer cells.

A Mitochondria-targeted AIEgen Labelled with 18 F for Breast Cancer Cell Imaging and Therapy.

A lack of efficient diagnostic tools for early and noninvasive diagnosis of breast cancer has restricted the clinical treatment effect. This problem might be addressed by the combination of aggregation-induced emission (AIE) fluorescence imaging and positron emission tomography (PET) with the dual advantages of high resolution and easy operation, and unlimited penetration and high sensitivity. Here, a mitochondria-targeted AIE luminogen (AIEgen) radiolabeled with 18 F was developed through a two-step radiochemical reaction by virtue of a prosthetic group. The obtained 18/19 F-Bz-CP imaging probe was examined by in vitro cell uptake and cell proliferation inhibition in two breast cancer cell lines, showing that the probe can efficiently target and locate in the mitochondria through the analysis of fluorescence imaging and PET simultaneously. Additionally, the probe can induce cancer cell apoptosis with the half maximal inhibitory concentration (IC50) of 4.8 μM for MCF-7 cells and 7.2 μM for T47D cells, indicating its potential application for breast cancer therapy.

RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma.

Background: Malignant glioma (MG) is an aggressive malignant brain tumor. Despite advances in multidisciplinary treatment, overall survival rates remain low. A trifluoroethyl amide derivative of 2-cyano-3-,12-dioxoolean-1,9-dien-28-oic acid (CDDO), CDDO–trifluoroethyl amide (CDDO–TFEA) is a nuclear erythroid 2-related factor 2/antioxidant response element pathway activator. RTA404 is used to inhibit proliferation and induce apoptosis in cancer cells. However, its effect on tumorigenesis in glioma is unclear. Methods: This in vitro study evaluated the effects of RTA404 on MG cells. We treated U87MG cell lines with RTA404 and performed assessments of apoptosis and cell cycle distributions. DNA content and apoptosis induction were subjected to flow cytometry analysis. The mitotic index was assessed based on MPM-2 expression. Protein expression was analyzed through Western blotting. Results: RTA404 significantly inhibited the cell viability and induced cell apoptosis on the U87MG cell line. The Annexin-FITC/PI assay revealed significant changes in the percentage of apoptotic cells. Treatment with RTA404 led to a significant reduction in the U87MG cells’ mitochondrial membrane potential. A significant rise in the percentage of caspase-3 activity was detected in the treated cells. In addition, these results suggest that cells pass the G2 checkpoint without cell cycle arrest by RTA404 treatment in the MPM-2 staining. An analysis of CHK1, CHK2, and p-CHK2 expression suggested that the DNA damage checkpoint system seems also to be activated by RTA404 treatment in established U87MG cells. Therefore, RTA404 may not only activate the DNA damage checkpoint system, it may also exert apoptosis in established U87MG cells. Conclusions: RTA404 inhibits the cell viability of gliomas and induces cancer cell apoptosis through intrinsic apoptotic pathway in Malignant glioma. In addition, the DNA damage checkpoint system seems also to be activated by RTA404. Taken together, RTA404 activated the DNA damage checkpoint system and induced apoptosis through intrinsic apoptotic pathways in established U87MG cells.

Targeting thioredoxin reductase by deoxyelephantopin from Elephantopus scaber triggers cancer cell apoptosis

Elevated expression of thioredoxin reductase (TrxR) is associated with the tumorigenesis and resistance to cancer chemoradiotherapy, highlighting the potential of TrxR inhibitors as anticancer drugs. Deoxyelephantopin (DET) is the major active ingredient of Elephantopus scaber and reveals potent anticancer activity. However, the potential mechanism of action and the cellular target of DET are still unknown. Here, we found that DET primarily targets the Sec residue of TrxR and irreversibly prohibits enzyme activity. Suppression of TrxR by DET leads to accumulation of reactive oxygen species and dysregulation in intracellular redox balance, eventually inducing cancer cell apoptosis mediated by oxidative stress. Noticeably, down-regulation of TrxR1 by shRNA increases cell sensitivity to DET. Collectively, targeting of TrxR1 by DET uncovers a novel mechanism of action in DET and deepens the understanding of developing DET as a potential chemotherapeutic agent for treating cancers.

A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer.

In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.

STING-mediated Syk Signaling Attenuates Tumorigenesis of Colitis‑associated Colorectal Cancer Through Enhancing Intestinal Epithelium Pyroptosis.

Stimulator of interferon genes (STING) has essential functions in the immune responses and can induce cancer cell apoptosis. However, it is not completely clear how STING plays a role in colitis-associated colorectal cancer (CAC) and whether it can trigger pyroptosis during the tumorigenesis of CAC. To investigate the role of STING-modulated pyroptosis in the development of CAC, STING knockout and Wild type mice were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to establish a murine CAC model. STING pharmacological agonist was used to further study the functions of STING signaling in the tumorigenesis. Moreover, STING endogenous ligand was employed to verify the effects of STING in human colon cancer cells. STING deficiency mice were more susceptible to CAC by reducing pyroptosis of tumor cells, whereas overactivation of STING with the agonist suppressed tumorigenesis of CAC. STING also managed CAC development by modulating tumor cells proliferation, adhesion, and invasion, as well as inflammatory response. The ex vivo studies indicated that STING could induce pyroptosis via spleen tyrosine kinase (Syk), and Syk knockdown weakened such pyroptotic tumor cells death. In addition, the visible physical interaction between STING and Syk was observed in colorectal tumor samples of CAC patients. STING-mediated Syk signaling may regulate the tumorigenesis of CAC by modulating pyroptosis of tumor cells, and modulation of STING/Syk serves as a novel therapeutic strategy for CAC therapy.

Engineering Exosomes Endowed with Targeted Delivery of Triptolide for Malignant Melanoma Therapy.

Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.

Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells.

The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, depending on the cellular context. This review summarizes the available information on the role of the Wnt/β-catenin pathway and its crosstalk with other signaling pathways in apoptosis induction in cancer cells and presents a modified dual-signal model for the function of β-catenin. Understanding the proapoptotic mechanisms induced by the Wnt/β-catenin pathway could open new therapeutic opportunities.

Gold-Bipyramid-Based Nanothernostics: FRET-Mediated Protein-Specific Sialylation Visualization and Oxygen-Augmenting Phototherapy against Hypoxic Tumor.

Despite several attempts, incorporating biological detection that supplies necessary biological information into therapeutic nanotheranostics for hypoxic tumor treatments is considered to be in its infancy. It is therefore imperative to consolidate biological detection and desirable phototherapy into a single nanosystem for maximizing theranostic advantages. Herein, we develop a versatile nanoprobe through combined fluorescence resonance energy transfer (FRET) and oxygen-augmenting strategy, namely APT, which enables glycosylation detection, O2 self-sufficiency, and collaborative phototherapy. Such APT nanoprobes were constructed by depositing platinum onto gold nano-bipyramids (Au NBPs), linking FITC fluorophore-labeled AS1411 aptamers for introducing FRET donors, and by conjugating G-quadruplex intercalated with TMPyP4 to their surfaces via the SH-DNA chain. By installing FRET acceptors on the glycan of targeted EpCAM glycoprotein using the metabolic glycan labeling and click chemistry, FRET signals appear on the cancerous cell membranes, not normal cells, when donors and acceptors are within an appropriate distance. This actualizes protein-specific glycosylation visualization while revealing glycan-based changes correlated with tumor progression. Interestingly, the deposited platinum scavenges excessive H2O2 as artificial nanoenzymes to transform O2 that alleviates tumor hypoxia and simultaneously elevates singlet oxygen (1O2) for inducing cancer cell apoptosis. Notably, the significant hyperthermia devastation was elicited via APT nanoprobes with phenomenal photothermal therapy (PTT) efficiency (71.8%) for thermally ablating cancer cells, resulting in synergistically enhanced photodynamic-hyperthermia therapy. Consequently, APT nanoprobes nearly actualized thorough tumor ablation while demonstrating highly curative biosafety. This work offers a new paradigm to rationally explore a combined FRET and oxygen-augmenting strategy with a focus on nanotheranostics for hypoxic tumor elimination.

CircASAP1 promotes the development of cervical cancer through sponging miR-338-3p to upregulate RPP25.

Circular RNAs have been identified as vital regulators to regulate the development of human cancers, including cervical cancer. Therefore, this study was designed to clarify the underlying mechanism of circASAP1 in cervical cancer. The real-time quantitative PCR assay was applied to quantify the expression levels of circASAP1, microRNA (miR)-338-3p, and ribonuclease P and MRP subunit p25 (RPP25) in cervical cancer tissues and cells. The cell proliferation ability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide and colony-forming assays. The protein expression levels of cyclin D1, proliferating cell nuclear antigen, and RPP25 were assessed by western blot assay. Flow cytometry assays were used to determine the apoptosis and cell cycle distribution of cervical cancer cells. The transwell assay was employed to test the migration and invasion abilities of cervical cancer cells. The interaction relationship between miR-338-3p and circASAP1 or RPP25 was confirmed by dual-luciferase reporter assay and RNA pull-down assay. The xenograft experiment was established to clarify the functional role of circASAP1 inhibition in vivo. CircASAP1 was overexpressed in cervical cancer tissues and cells compared with negative groups. Additionally, the loss-of-functional experiments implied that knockdown of circASAP1 impeded proliferation, migration, and invasion while induced apoptosis and cell cycle arrest in cervical cancer cells along with repressed tumor growth in vivo through regulation of miR-338-3p. In addition, RPP25 was a target mRNA of miR-338-3p, and overexpression of miR-338-3p suppressed proliferation, migration, and invasion while induced apoptosis and cell cycle arrest in cervical cancer cells by suppressing RPP25 expression. Mechanistically, circASAP1 could function as a sponge for miR-338-3p to increase the expression of RPP25, and further regulated proliferation, migration, invasion, apoptosis, and cell cycle program of cervical cancer cells, which might be potential markers for cervical cancer diagnosis.

Membrane-Interacting DNA Nanotubes Induce Cancer Cell Death.

DNA nanotechnology offers to build nanoscale structures with defined chemistries to precisely position biomolecules or drugs for selective cell targeting and drug delivery. Owing to the negatively charged nature of DNA, for delivery purposes, DNA is frequently conjugated with hydrophobic moieties, positively charged polymers/peptides and cell surface receptor-recognizing molecules or antibodies. Here, we designed and assembled cholesterol-modified DNA nanotubes to interact with cancer cells and conjugated them with cytochrome c to induce cancer cell apoptosis. By flow cytometry and confocal microscopy, we observed that DNA nanotubes efficiently bound to the plasma membrane as a function of the number of conjugated cholesterol moieties. The complex was taken up by the cells and localized to the endosomal compartment. Cholesterol-modified DNA nanotubes, but not unmodified ones, increased membrane permeability, caspase activation and cell death. Irreversible inhibition of caspase activity with a caspase inhibitor, however, only partially prevented cell death. Cytochrome c-conjugated DNA nanotubes were also efficiently taken up but did not increase the rate of cell death. These results demonstrate that cholesterol-modified DNA nanotubes induce cancer cell death associated with increased cell membrane permeability and are only partially dependent on caspase activity, consistent with a combined form of apoptotic and necrotic cell death. DNA nanotubes may be further developed as primary cytotoxic agents, or drug delivery vehicles, through cholesterol-mediated cellular membrane interactions and uptake.

Polymer‐Based Drug‐Free Therapeutics for Anticancer, Anti‐Inflammatory, and Antibacterial Treatment

Inside Front Cover: The precise biorecognition of natural binding motifs by multiple vectors on the polymer construct is a crucial part of the designing of polymer-based drug-free macromolecular therapeutics, a novel class of therapeutics with tailored macromolecular design. It leads to the induction of cancer cell apoptosis or depletion of the efficacy of tumor-associated proteins. This is reported by Tomáš Etrych and co-workers in article 2100135.

Oxygen‐Independent Photocleavage of Radical Nanogenerator for Near‐IR‐Gated and H2O‐Mediated Free‐Radical Nanotherapy

AbstractThe oxygen‐dependent nature and limited penetration capacity of visible light render the low efficiency of photodynamic therapy in hypoxic and deep‐seated tumors. Therefore, the development of oxygen‐free photoactivated chemotherapy (PACT) to generate cytotoxic reactive oxygen species by near‐IR (NIR) light‐cleavable photocages is in high demand. Here, an oxygen‐irrelevant PACT strategy based on NIR light‐triggered hydroxyl radicals (•OH) generation is developed for free‐radical nanotherapy. Blebbistatin‐loaded upconversion of mesoporous silica nanoparticles (UCSNs‐B) is established to facilitate the high loading efficiency of blebbistatin and implement the efficient transformation of NIR light into blue light for unprecedented direct photorelease of oxygen‐independent •OH. Under NIR laser irradiation, UCSNs‐B converted NIR light into blue light, thus enabling the photocleavage of blebbistatin to induce the burst of •OH. The •OH burst under NIR laser irradiation further induces cancer cell apoptosis and significant suppression of hypoxic tumors. In addition, the gadolinium ion (Gd3+)‐doped UCSNs‐B are used as contrast agents in magnetic resonance imaging to facilitate real‐time monitoring of the therapeutic processes. This study effectively demonstrates that the UCSNs‐B act as NIR light‐triggered photocages to facilitate oxygen‐irrelevant •OH bursts, thus providing insights into the development of efficient PACT nanoagents for cancer treatment.

Aloe vera gel extract: Safety evaluation for acute and chronic oral administration in Sprague-Dawley rats and anticancer activity in breast and lung cancer cells

Ethnopharmacological relevanceAloe vera (L.) Burm. f. is a typical traditional Chinese medicine (TCM) collected in the Pharmacopoeia of the People's Republic of China (version 2015). It has been traditionally used for the treatment of constipation, and its potential therapeutic activities have been widely evaluated, including anti-tumor, anti-inflammatory and immune regulatory effects. The wide application of Aloe vera in food and therapy has raised safety issues and there are multiple safety assessments with a diverse toxicity and adverse effects from clinics and animals. Aim of the studyThis study aimed to investigate the safety of Aloe vera barbadensis extract C (AVBEC) in rats and analyze its anticancer activity in cell lines. Materials and methodsWe administrated AVBEC orally in an acute toxicity study and a 6-month chronic toxicity study to observe and confirm its safety in Sprague-Dawley (SD) rats. Additionally, we explored the cytotoxicity of AVBEC in cancer cells and non-cancer cells. We further investigated the anti-tumor activity of AVBEC, and in the meantime, probed the function of component from AVBEC. ResultsNo deaths or substance-relative toxicity were observed in the acute toxicity study or the 6-month chronic toxicity study with doses of 44.8 g·kg-1 and 4.48 g·kg-1, respectively. In the chronic toxicity study, AVBEC did not cause organ toxicity, including crucial organ structure and chemical function, and peripheral and central immune system damage. Additionally, we found that AVBEC could induce cancer cell apoptosis with a relatively higher apoptotic ratio than in non-cancer cells by decreasing adenosine triphosphate (ATP) concentration and enhancing reactive oxygen species (ROS) production. We also identified components in AVBEC using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) and probed the function of malic acid. This demonstrated that under the same circumstances, malic acid induced cell necrosis in cancer cells and non-cancer cells, while AVBEC did not. ConclusionsThese results reveal a novel mechanism of aloe gel extract in regulating cancer cell apoptosis via modulating the mitochondrial metabolism and imply a possible application of AVBEC for the treatment of malignant cancer with the safety evaluation from rats and anticancer investigation from cancer cells and non-cancer cells.

Anti-Proliferative and Anti-Migratory Activities of Hispidulin on Human Melanoma A2058 Cells.

Melanoma represents less than 5% of skin cancers, but is the most lethal, mainly because of its high-metastatic potential and resistance to various therapies. Therefore, it is important to develop effective treatments, especially chemotherapeutic drugs with cytotoxicity, anti-metastaticity, and few side effects. One such natural product is hispidulin, a flavone distributed in plants of the Asteraceae. Previous studies have demonstrated that hispidulin has various pharmacological benefits, such as anti-tumor, anti-inflammation, and anti-allergic effects. This study aims to explore the effects of hispidulin against melanoma in vitro and in vivo. Results revealed that hispidulin selectively decreased the cell viability of A2058 cells in a dose- and time-dependent manner. Hispidulin induced cells accumulated in the sub-G1 phase via activating caspase 8 and 9, increased cleaved caspase 3, and cleaved PARP expression. Hispidulin was able to decrease AKT and ERK phosphorylation, which facilitated cell growth and survival. Moreover, hispidulin promoted reactive oxygen species generation in cells and suppressed cell migration through downregulated matrix metalloproteinase-2 expression. Hispidulin significantly inhibited tumor growth in a xenograft model. Based on these results, hispidulin produces its anti-melanoma effects by inducing cancer cell apoptosis and reducing its migration. Therefore, we suggest hispidulin as a potent therapeutic candidate for melanoma treatment.

Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray

X-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks. We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles. IPO were loaded onto tumor spheroids and the spheroids were irradiated with 33.2 keV monochromatic X-ray. After incubation in CO2 incubator, destruction of tumor spheroids was observed which was accompanied by apoptosis induction, as determined by the TUNEL assay. By employing the γH2AX assay, we detected double strand DNA cleavages immediately after the irradiation. These results suggest that IPO first generate double strand DNA breaks upon X-ray irradiation followed by apoptosis induction of cancer cells. Use of three different monochromatic X-rays having energy levels of 33.0, 33.2 and 33.4 keV as well as X-rays with 0.1 keV energy intervals showed that the optimum effect of all three events (spheroid destruction, apoptosis induction and generation of double strand DNA breaks) occurred with a 33.2 keV monochromatic X-ray. These results uncover the preferential effect of K-edge energy X-ray for tumor spheroid destruction mediated by iodine containing nanoparticles.

CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell

The C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins’ regulatory roles in genomic stability and DNA repair in HGSOC. In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells. Interesting, blast through TCGA tumor cases, patients with CtBP2 genetic alternation had a significantly longer overall survival time than unaltered patients. Together, these results revealed that CtBP1/2 play a different regulatory role in genomic stability and DSBs repair pathway bias in serous ovarian cancer cells. It is possible to generate novel potential targeted therapy strategy and translational application for serous ovarian carcinoma patients with a predictable better clinical outcome.

Emerging Roles of Pseudogene RNAs in Antitumor and Antiviral Immunity

Innate immunity mediates anti-tumor responses through a variety of mechanisms including stimulation of cytokine production, activation of cytotoxic immune cells, and induction of cancer cell apoptosis. Together, these anti-tumor defense mechanisms can increase the efficacy of chemo- or immunotherapies. Intriguingly, recent evidence suggests that innate immune responses are intricately regulated not only by exogenous non-self RNA but also by host-derived RNAs such as pseudogene transcripts.