Apoptosis-inducing Properties Research Articles

Lanostane Triterpenes, Flavanones and Acetogenins from the Roots of Uvaria siamensis and Their Cytotoxic Activity.

Our phytochemical investigation of the roots of Uvaria siamensis led to the isolation of two new lanostane triterpenes, 3-acetylpolycarpol (1) and 15-acetylpolycarpol (2), as well as 15 known compounds (3-17). The structures of the isolated compounds were elucidated by an analysis of spectroscopic data. Compounds 1-9 were tested against nonsmall cell lung cancer cells (A549) and human cervical carcinoma cells (HeLa) using an MTT assay. Polycarpol (3) and uvariamicin-II (9) exhibited potent cytotoxicity against A549 cancer cells, while 15-acetylpolycarpol (2) and pinocembrin (4) displayed potent cytotoxicity against HeLa cancer cells. Further analysis of the apoptosis-inducing properties revealed that uvariamicin-II (9) and pinocembrin (4) induced apoptosis in a dose-dependent manner in A549 and HeLa cells, respectively. These two compounds also showed weak cytotoxicity toward Vero cells.

Comparison of the Cytotoxic Mechanisms of Different Garlic (Allium sativum L.) Cultivars with the Crucial Involvement of Peroxisome Proliferator-Activated Receptor Gamma.

Garlic (Allium sativum L.) is one of the oldest known useful plants, valued for thousands of years. This plant contains many biologically active compounds, including polyphenols, sterols, cysteine-sulfoxides, carbohydrates, proteins, and amino acids. The aim of our study was to compare the antioxidant potential, cytotoxicity, and apoptosis induction properties of four garlic cultivars-Harnaś, Ornak, Violeta, and Morado-in human squamous carcinoma (SCC-15) cells, colon adenocarcinoma (CACO-2) cells, and normal fibroblasts (BJ). Additionally, we investigated the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARγ), microtubule-associated protein 1 light chain 3 (LC3A), superoxide dismutase 1 (SOD1), and catalase (CAT) after treatment with the studied garlic extracts. Our study demonstrated that high ROS production was correlated with the strong toxicity of the garlic extracts. All studied extracts produced a lesser increase in ROS in normal BJ fibroblasts and were less toxic to these cells. The expression patterns of PPARγ, LC3A, SOD1, and CAT, along with chromatographic analysis, suggest differing mechanisms among the garlic cultivars. The highest levels of catechin, a known PPARγ agonist, were detected in the Harnaś (3.892 µg/mL) and Ornak (3.189 µg/mL) cultivars. A high catechin content was correlated with similar changes in PPARγ and related SOD1 and LC3A. Our findings showed the health-promoting and anticancer properties of garlic. However, we could not definitively identify which polyphenol or how it is involved in PPARγ activation. Further studies are required to elucidate the role of PPARγ in the mechanism of action of garlic extracts.

CO-loaded hemoglobin/EGCG nanoparticles functional coatings for inflammation modulation of vascular implants.

During the implantation process of cardiovascular implants, vascular damage caused by inflammation occurs, and the inflammatory process is accompanied by oxidative stress. Currently, carbon monoxide (CO) has been demonstrated to exhibit various biological effects including vasodilatation, antithrombotic, anti-inflammatory, apoptosis-inducing and antiproliferative properties. In this study, hemoglobin/epigallocatechin-3-gallate (EGCG) core-shell nanoparticle-containing coating on stainless steel was prepared for CO loading and inflammation modulation. Inspired by strong coordination ability with CO, hemoglobin nanoparticle was first prepared and encapsulated into EGCG metal-phenolic networks. A polydopamine (PDA) linking layer was then coated on 316 stainless steel, and the hemoglobin/EGCG nanoparticles were loaded with the subsequent PDA deposition. It showed that the maximum release amount of CO by the coating was 17.0 nmol/cm2 in 48 h. In vitro evaluations conducted in a simulated inflammatory environment revealed that the coating, which released CO from hemoglobin/EGCG nanoparticles, effectively mitigated the lipopolysaccharide-induced inflammatory response in macrophages. Specifically, it decreased the expression of tumor necrosis factor-α, increased the expression of interleukin-10, suppressed the polarization of macrophages toward the M1 phenotype and reduced intracellular reactive oxygen species (ROS). Furthermore, under simulated oxidative stress conditions, the coating decreased the apoptosis of endothelial cells induced by oxidative stress and down-regulated intracellular ROS levels. In vivo implantation results further confirmed that the coating, with its hemoglobin/EGCG nanoparticles and CO release capabilities, reduced macrophage-mediated inflammatory responses and modulated the polarization phenotype of macrophages.

A New Class of Gold(I) NHC Complexes with Proapoptotic and Resensitizing Properties towards Multidrug Resistant Leukemia Cells Overexpressing BCL-2.

From previous studies, it is evident that metal-organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes 1 and 2 are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex 1 targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex 1 involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.

Ethyl pyruvate attenuates cellular adhesion and proliferation of diffuse large B-cell lymphoma by targeting c-Jun.

Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl pyruvate (EP) is a derivative of pyruvic acid and found to have potent anti-tumor properties. Despite its potential benefits, the impact of EP on DLBCL remains ambiguous. Our objective is to elucidate the role of EP in modulating the development of DLBCL. Analysis of cholecystokinin-8 (CCK-8) revealed that treatment with EP significantly diminished the viability of DLBCL cells. Furthermore, EP administration suppressed colony formation and hindered cell adhesion and invasion in DLBCL cells. Examination of cell cycle progression showed that EP treatment induced arrest at the G1 phase and subsequently reduced the S phase population in DLBCL cells. EP treatment consistently exhibited apoptosis-inducing properties in Annexin-V assays, and notably downregulated the expression of Bcl-2 while increasing levels of proapoptotic cleaved caspase 3 and BAX in DLBCL cells. Additionally, EP treatment decreased the overexpression of c-Jun in c-Jun-transfected DLBCL cells. Further, EP demonstrated DNA-damaging effects in TUNEL assays. In vivo, xenograft animal models revealed that EP treatment significantly mitigated DLBCL tumor growth and suppressed DLBCL cell adhesion to bone marrow stromal cells. In summary, these findings suggest that EP mitigates DLBCL progression by inducing apoptosis, inducing cell cycle arrest, and promoting DNA damage.

Cytotoxic and apoptosis-inducing properties of Staphylococcus aureus cytoplasmic extract on lung cancer cells: Insights from MTT assay and bax/bcl-2 gene expression analysis

BackgroundLung cancer ranks as the second most prevalent cancer in both men and women and stands as one of the most prevalent and lethal malignancies globally. In recent decades, the therapeutic potential of bacteria has gained recognition in pharmaceutical and therapeutic research. While bacteria have historically been associated with cancer causation, recent studies have unveiled their potential as efficacious agents for targeted cancer therapy. However, limited data exist on the characterization and impact of Staphylococcus aureus (S. aureus) extract on lung cancer cell lines. Consequently, this study aims to investigate the effect of S. aureus extract on inducing apoptosis in A549, a lung cancer cell line, and MRC-5, a lung normal cell line, by evaluating the expression levels of the bax and bcl-2 genes. MethodsInitially, cytoplasmic extract of S. aureus was prepared using the sonication technique. The protein concentration was determined via the Bradford assay, and the presence of proteins was confirmed using SDS-PAGE. A549, representing a lung cancer cell line, and MRC-5, representing a lung normal cell line, were exposed to varying concentrations of bacterial extract, and cell viability was assessed using the MTT assay. Subsequently, the expression levels of the bax and bcl-2 genes were quantified utilizing the Real-Time PCR method. ResultsCytoplasmic extract derived from S. aureus demonstrated the ability to modulate the expression levels of apoptotic genes. Relative to the control group, the bax gene exhibited a fivefold overexpression, while the expression of the bcl-2 gene decreased by more than half compared to the control. Furthermore, the results of the MTT assay indicated that the bacterial cytoplasmic extract exhibited concentration-dependent cytotoxicity on cancer cells, highlighting a significant increase in cell death with escalating concentrations. ConclusionsThis research highlights the potential of S. aureus extract for targeted lung cancer therapy by promoting cancer cell apoptosis while sparing normal cells. These findings open up exciting possibilities for innovative cancer treatments and improved patient outcomes, emphasizing the promise of S. aureus extract in the fight against lung cancer.

Biogenic Ag-doped ZnO nanostructures induced cytotoxicity in luminal A and triple-negative human breast cancer cells.

Aim: To evaluate the apoptosis-inducing properties of undoped and silver-doped-zinc-oxide nanoparticles (SDZONs) synthesized using Boswellia serrata against MCF-7 (Luminal-A) and MDA-MB-231(Triple-negative) breast cancer cell lines.Methodology: Nanostructures were developed by facile biohydrothermal method and characterized by x-ray diffraction (XRD), Fourier transform infrared (FTIR), and high resolutiontransmission electron microscopy (HR-TEM). The comparative effect of doping and dose concentration of nanostructures on cytotoxicity was measured using MTT and trypan-blue-exclusion assay.Results: SDZONs exhibited greater cytotoxicity (20.71%, 27.31% cell viability) as compared with undoped nanostructures (35.81%, 37.08% cell viability) against MCF 7 and MDA-MB-231, respectively.Conclusion: The activity of biogenic nanostructures was highly dependent on doping, dose, and type of cell lines used. The novel biogenic SDZONs could be exploited as a promising, cost-effective, and environmentally benign strategy to curb breast cancer.

(2,6-Dimethylphenyl)arsonic Acid Induces Apoptosis through the Mitochondrial Pathway, Downregulates XIAP, and Overcomes Multidrug Resistance to Cytostatic Drugs in Leukemia and Lymphoma Cells In Vitro.

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.

Integrated gene co-expression network analysis and experimental validation revealed potential targets of human urine extract CDA-II in treating chronic myeloid leukemia

BackgroundCell differentiation agent II (CDA-II) exhibits potent anti-proliferative and apoptosis-inducing properties against a variety of cancer cells. However, its mechanism of action in chronic myeloid leukemia (CML) remains unclear. MethodsCell counting Kit 8 (CCK-8) and flow cytometry were used to investigate the effects of CDA-II on the biological characteristics of K562 cells. Gene (mRNA and lncRNA) expression profiles were analyzed by bioinformatics to screen differentially expressed genes and to perform enrichment analysis. The Pearson correlation coefficients of lncRNAs and mRNAs were calculated using gene expression values, and a lncRNA/mRNA co-expression network was constructed. The MCODE and cytoHubba plugins were used to analyze the co-expression network. ResultsThe Results, derived from CCK-8 and flow cytometry, indicated that CDA-II exerts dual effects on K562 cells: it inhibits their proliferation and induces apoptosis. From bioinformatics analysis, we identified 316 mRNAs and 32 lncRNAs. These mRNAs were predominantly related to the meiotic cell cycle, DNA methylation, transporter complex and peptidase regulator activity, complement and coagulation cascades, protein digestion and absorption, and cell adhesion molecule signaling pathways. The co-expression network comprised of 163 lncRNA/mRNA interaction pairs. Notably, our analysis results implicated clustered histone gene families and five lncRNAs in the biological effects of CDA-II on K562 cells. ConclusionThis study highlights the hub gene and lncRNA/mRNA co-expression network as crucial elements in the context of CDA-II treatment of CML. This insight not only enriches our understanding of CDA-II's mechanism of action but also might provide valuable clues for subsequent experimental studies of CDA-II, and potentially contribute to the discovery of new therapeutic targets for CML.

Oridonin from Rabdosia rubescens: An emerging potential in cancer therapy - A comprehensive review.

Cancer incidences are rising each year. In 2020, approximately 20 million new cancer cases and 10 million cancer-related deaths were recorded. The World Health Organization (WHO) predicts that by 2024 the incidence of cancer will increase to 30.2 million individuals annually. Considering the invasive characteristics of its diagnostic procedures and therapeutic methods side effects, scientists are searching for different solutions, including using plant-derived bioactive compounds, that could reduce the probability of cancer occurrence and make its treatment more comfortable. In this regard, oridonin (ORI), an ent-kaurane diterpenoid, naturally found in the leaves of Rabdosia rubescens species, has been found to have antitumor, antiangiogenesis, antiasthmatic, antiinflammatory, and apoptosis induction properties. Extensive research has been performed on ORI to find various mechanisms involved in its anticancer activities. This review article provides an overview of ORI's effectiveness on murine and human cancer populations from 1976 to 2022 and provides insight into the future application of ORI in different cancer therapies.

Sesamol as a potent anticancer compound: from chemistry to cellular interactions.

Sesamol (SM), a well-known component isolated from sesame seeds (Sesamum indicum), used in traditional medicines in treating numerous ailments. However, numerous molecular investigations revealed the various mechanisms behind its activity, emphasizing its antiproliferative, anti-inflammatory, and apoptosis-inducing properties, preventing cancer cell spread to distant organs. In several cells derived from various malignant tissues, SM-regulated signal transduction pathways and cellular targets have been identified. This review paper comprehensively describes the anticancer properties of SM and SM-viable anticancer drugs. Additionally, the interactions of this natural substance with standard anticancer drugs are examined, and the benefits of using nanotechnology in SM applications are explored. This makes SM a prime example of how ethnopharmacological knowledge can be applied to the development of contemporary drugs.

Synthesis, characterization, and biomedical evaluation of ethylene-bridged tetra-NHC Pd(ii), Pt(ii) and Au(iii) complexes, with apoptosis-inducing properties in cisplatin-resistant neuroblastoma cells.

Synthesis and characterization of the first two cyclic ethylene-bridged tetradentate NHC ligands, with an unsaturated (imidazole) and saturated backbone (2-imidazoline), are described. Complexes of both ligands containing palladium(ii) have been obtained. For platinum(ii) and gold(iii), only the unsaturated tetracarbene complexes could be isolated. The attempts to synthesize a methylene-bridged 2-imidazoline macrocycle are also described. Furthermore, a novel bisimidazolinium ligand precursor and its open-chain PdII and PtII tetracarbene complexes are obtained. Finally, it is shown that the unsaturated gold(iii) tetracarbene is able to induce apoptosis in malignant SK-N-AS neuroblastoma cells via the mitochondrial and ROS pathway and overcomes resistance to cisplatin in vitro.

Discovery of Potent Indolyl-Hydrazones as Kinase Inhibitors for Breast Cancer: Synthesis, X-ray Single-Crystal Analysis, and In Vitro and In Vivo Anti-Cancer Activity Evaluation.

According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer statistics continues to rise, it is imperative to explore new avenues in the ongoing battle against this disease. Therefore, a number of new indolyl-hydrazones were synthesized by reacting the ethyl 3-formyl-1H-indole-2-carboxylate 1 with thiosemicarbazide, semicarbazide.HCl, 4-nitrophenyl hydrazine, 2,4-dinitrophenyl hydrazine, and 4-amino-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione to afford the new hit compounds, which were assigned chemical structures as thiosemicarbazone 3, bis(hydrazine derivative) 5, semicarbzone 6, Schiff base 8, and the corresponding hydrazones 10 and 12 by NMR, elemental analysis, and X-ray single-crystal analysis. The MTT assay was employed to investigate the compounds' cytotoxicity against breast cancer cells (MCF-7). Cytotoxicity results disclosed potent IC50 values against MCF-7, especially compounds 5, 8, and 12, with IC50 values of 2.73 ± 0.14, 4.38 ± 0.23, and 7.03 ± 0.37 μM, respectively, compared to staurosproine (IC50 = 8.32 ± 0.43 μM). Consequently, the activities of compounds 5, 8, and 12 in relation to cell migration were investigated using the wound-healing test. The findings revealed notable wound-healing efficacy, with respective percentages of wound closure measured at 48.8%, 60.7%, and 51.8%. The impact of the hit compounds on cell proliferation was assessed by examining their apoptosis-inducing properties. Intriguingly, compound 5 exhibited a significant enhancement in cell death within MCF-7 cells, registering a notable increase of 39.26% in comparison to the untreated control group, which demonstrated only 1.27% cell death. Furthermore, the mechanism of action of compound 5 was scrutinized through testing against kinase receptors. The results revealed significant kinase inhibition, particularly against PI3K-α, PI3K-β, PI3K-δ, CDK2, AKT-1, and EGFR, showcasing promising activity, compared to standard drugs targeting these receptors. In the conclusive phase, through in vivo assay, compound 5 demonstrated a substantial reduction in tumor volume, decreasing from 106 mm³ in the untreated control to 56.4 mm³. Moreover, it significantly attenuated tumor proliferation by 46.9%. In view of these findings, the identified leads exhibit promises for potential development into future medications for the treatment of breast cancer, as they effectively hinder both cell migration and proliferation.

Effect of Black Rice Bran ‘Sembada Hitam’ on T47D Breast Cancer Cells

Indonesians have a rich tradition of incorporating black rice into their diet as a functional food due to its high antioxidant content. This research investigates the effects of the ethanolic extract of "Sembada Hitam" black rice bran on T47D breast cancer cells, specifically its cytotoxic, cell growth, and apoptotic induction properties. The MTT assay method was used to evaluate the cytotoxicity of the black rice bran extract on T47D cells after 24 and 48 hours of incubation. The acridine orange/propidium iodide (AO/PI) dye double staining method was employed to assess the apoptosis-inducing properties of the extract. Additionally, a cell growth assay was conducted to evaluate the effect of the extract on cell growth, with observations recorded on days 0, 3, and 6. The results revealed that the ethanolic extract of black rice bran "Sembada Hitam," when administered at various concentrations ranging from 7.81 to 1000 µg/mL, did not exhibit cytotoxic effects on T47D cells during the 24 and 48 hours of incubation. The cell growth assay revealed that T47D cells treated with the ethanolic extract of "Sembada Hitam" black rice bran at concentrations of 250 and 500 µg/mL exhibited lower growth rates than the 1% DMSO group from the 3rd to 6th day after incubation. The ethanolic extract of "Sembada Hitam" at concentrations of 250, 500, and 1000 µg/mL resulted in cell death of 10.64 ± 2.98%, 9.99 ± 5.87%, and 5.84 ± 0.78%, respectively. In conclusion, this study found that the ethanolic extract of "Sembada Hitam" black rice bran did not demonstrate significant cytotoxic effects on T47D breast cancer cells and is, therefore, unlikely to be a suitable candidate for an anti-cancer agent.

Catechin-Functionalized Cationic Lipopolymer Based Multicomponent Nanomicelles for Lung-Targeting Delivery.

Catechins from green tea are one of the most effective natural compounds for cancer chemoprevention and have attracted extensive research. Cancer cell-selective apoptosis-inducing properties of catechins depend on efficient intracellular delivery. However, the low bioavailability limits the application of catechins. Herein, a nano-scaled micellar composite composed of catechin-functionalized cationic lipopolymer and serum albumin is constructed. Cationic liposomes tend to accumulate in the pulmonary microvasculature due to electrostatic effects and are able to deliver the micellar system intracellularly, thus improving the bioavailability of catechins. Albumin in the system acts as a biocompatible anti-plasma absorbent, forming complexes with positively charged lipopolymer under electrostatic interactions, contributing to prolonged in vivo retention. The physicochemical properties of the nano-micellar complexes are characterized, and the antitumor properties of catechin-functionalized materials are confirmed by reactive oxygen species (ROS), caspase-3, and cell apoptosis measurements. The role of each functional module, cationic polymeric liposome, and albumin is revealed by cell penetration, in vivo animal assays, etc. This multicomponent micellar nanocomposite has the potential to become an effective vehicle for the treatment of lung diseases such as pneumonia, lung tumors, sepsis-induced lung injury, etc. This study also demonstrates that it is a great strategy to create a delivery system that is both tissue-targeted and biologically active by combining cationic liposomes with the native bioactive compound catechins.

Plumbago zeylanica L. exhibited potent anticancer activity in Ehrlich ascites carcinoma bearing Swiss albino mice

ObjectivesWe investigated the anticancer activity of the PzMH fraction (hexane fraction) extracted from the roots of Plumbago zeylanica L., an ethnomedicinally significant plant widely distributed in India. MethodsThe PzMH fraction was obtained through rigorous extraction and purification processes. In vitro cytotoxicity assays were performed to assess its effects on Ehrlich ascites carcinoma (EAC) cells. Acute toxicity studies were conducted to evaluate its safety profile. An in vivo study was carried out on EAC-bearing Swiss albino mice to assess its anticancer efficacy. Flow cytometric and microscopic analyses were done to examine the induction of cell death by the PzMH fraction. Western blot analysis was used to investigate the molecular mechanisms involved. ResultsThe PzMH fraction exhibited a significant cytotoxic effect in vitro, resulting in 50% cell death in EAC cells at low concentrations. The calculated GI50 value for the PzMH fraction was 42.74 µg/ml, demonstrating a comparable efficacy to the standard drug 5-fluoro uracil (GI50 = 43.38 µg/ml). The safety of therapeutic doses was confirmed through acute toxicity studies, which yielded an LD50 value of 500 mg/kg body weight. In the in vivo study, the PzMH fraction demonstrated a substantial 79.05% inhibition in the growth of EAC cells at the 300 mg/kg body weight dose of PzMH fraction. Flow cytometric and microscopic analyses revealed distinct apoptotic features in EAC cells treated with the PzMH fraction. Cell cycle analysis showed a significant arrest at the G0/G1 stage following treatment. PzMH treatment elicited a response characterized by escalated levels of cleaved caspases-3 and −9, while concurrently leading to a decreased expression of the Bcl2 protein, as evidenced by Western blot analysis. ConclusionsThe current research provides empirical evidence supporting the anticancer activity of the PzMH fraction extracted from P. zeylanica. The observed cytotoxicity, safety, and apoptosis-inducing properties make it a promising candidate for further investigation as a potential cancer therapy. Further exploration of its phytochemical composition, including major compounds such as 4-hydroxybenzaldehyde, trans-cinnamic acid, plumbagin and lawsone, contributes to our understanding of its mechanisms of action.

Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques.

Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the "shock-and-kill" strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the "shock-and-kill" strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.

Investigating the Anti-tumor and Apoptosis-inducing Effects of Coumarin Derivatives as Potent 15-Lipoxygenase Inhibitors on PC-3 Prostate Cancer Cells.

Prostate cancer is the second most prevalent cancer among men. Despite different treatments, including surgery, chemotherapy, radiation therapy, hormone therapy and immunotherapy for this disease, patients ultimately progress to advanced states. Thus, there is a need for new treatment options targeting cell growth and apoptosis to better control the proliferation and metastasis of these cells. There are many reports indicating overexpression of the 15-lipoxygenase-1 (15-LOX-1) enzyme in prostate tumors. Studies have also shown that inhibition of this enzyme prevents the progression of prostate cancer. This study was conducted to assess the anti-cancer properties of some coumarin derivatives as possible 15- LOX-1 inhibitors, on PC-3 prostate cancer cells. In this study, the activity of 15-LOX-1 was evaluated in PC-3 cells by a spectrophotometric assay. In addition, due to high similarity between the 15-LOX-1 and soybean 15-lipoxygenase (SLO) (L1; EC 1, 13, 11, 12) active sites, the soybean SLO was used to investigate inhibitory effects of synthetic coumarin compounds 8- isopentenyloxycoumarin (8-IC), 8-isopentenyloxy-3-carboxycoumarin (8-ICC), 8-geranyloxycoumarin (8-GC), 8- geranyloxy-3-carboxycoumarin (8-GCC), and 8-farnesyloxy-3-carboxycoumarin (8-FCC) on this enzyme. Moreover, the cytotoxic and anticancer effects of the coumarin compounds were examined on PC-3 (Prostate Cancer) and HDF-1 (Human Dermal Fibroblast) cells by alamarBlue assay. Finally, apoptosis-inducing effects of all synthetic compounds were determined by flow cytometry. The IC50 values obtained by the alamarBlue test revealed that 8-IC, 8-GC and 8-GCC had cytotoxic effects on PC-3 cells. Treating both PC-3 and HDF-1 cells with 8-ICC and 8-FCC did not significantly reduce cell number. Furthermore, the IC50 values of 8-IC on HDF-1 cells showed cytotoxic effects, while treating these cells with 8-GC and 8- GCC did not show any significant cytotoxicity on these normal human fibroblasts. Assessing the ability of 4-MMPB (as a specific inhibitor of 15-LOX-1), 8-GC, and 8-GCC compounds to inhibit SLO revealed that these compounds exerted strong 15-LOX-1 inhibitory activity, while 8-IC and 8-FCC had a weak inhibitory effect and also 8-ICC showed no inhibitory effect on SLO enzyme. In addition, flow cytometric analysis by FITC (fluorescein isothiocyanate)- annexin V and propidium iodide showed that treatment with IC50 values of 8-GC and 8-GCC induced apoptosis in 35.2% and 30.8% of PC-3 cells, respectively. Thus, 8-GC and 8-GCC can be introduced as effective anticancer agents with apoptosis-inducing properties. Furthermore, our results suggest that the cytotoxic effects of these compounds might be related to the inhibition of 15-LOX-1 enzyme in PC-3 cells. On the other hand, the cytotoxic effects of 8-IC might be due to the inhibition of other signaling pathways in PC-3 cells. However, further in vivo experiments are required to determine the exact mechanisms involved in the anticancer effects of these coumarin compounds.

Anticancer activity of Inula graveolensby induction of ROS-independent apoptosis and suppression of IL6-IL8 in cervical cancer cells

Cancer is an important disease that causing to deaths in the world. Cervical cancer is one of the most common among women and must be treated quickly to prevent cell proliferation. Natural products have been used for cancer treatment due to their antiproliferative and apoptosis induction properties. In the present study, we aimed to determine the antiproliferative and apoptosis induction activities of methanol extract of Inula graveolens(IGME) in the human cerival cancer cell line (HeLa). Antiproliferative activity of IGME was evaluated by using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) method. Apoptosis induction activity was determined by AnnexinV/propodium iodide staining withFACS. ROS induction was determined by DCFH-DA (2′,7′-Dichlorofluorescin diacetate) staining. Interleukin 6 and 8 levels (IL-6 and IL-8) were determined by the Elisa method. IGME exhibited antiproliferative effect and induced apoptosis in the HeLa cells. IL-6, IL-8 and intracellular ROS levels were decreased after treatment of IGME. Consequently, IGME was found to have antiproliferative and apoptosis induction activities as an indicator of the anticancer activity.

Composition Analysis of Salsola grandis and Its Effects on Colon Cancer Cells.

The success of drug treatment of colon cancer (CC), which is in the top three in terms of incidence and mortality among all cancers, is adversely affected by reasons, such as severe side effects and chemoresistance. Clinical, epidemiological and experimental studies have indicated the need for developing new alternative drugs for the treatment of CC. Plants are an important source of traditional medicines that have proven to be highly beneficial for the treatment of CC. In this study, we aimed to reveal the antioxidant properties and anti-carcinogenic activity of Salsola grandis methanol extract (SGME) on HT-29. For this purpose, we used spectrophotometric methods to determine the antioxidant properties of SGME and LC-MS/MS analysis to measure the phenolic acid composition. We applied 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, the thiazolyl blue (MTT) method, to evaluate its effects on cell viability and ELISA assay, realtime PCR, and western blot method to reveal its effects on apoptosis. Spectrophotometric analyzes showed that SGME has the highest phenolic acid content, inhibits plasma lipid peroxidation and shows chelating activity and radical scavenging activity. Gene and protein expression analysis revealed the effects of SGME treatment on apoptosis genes/proteins. These findings showed that SGME has anticarcinogenic activity on CC due to its antioxidant, cell viability- suppressing and apoptosis-inducing properties.