Powerful Cytotoxic Effect Research Articles

Sensors of Intracellular Nucleic Acids Activating STING-Dependent Production of Interferons in Immunocompetent Cells

Currently, foreign DNA or RNA sensor proteins, which play an important role in innate immunity, are of great interest as a new avenue for cancer immunotherapy. Agonists of these proteins can activate signaling cascades in immune cells that cause the production of cytokines, in particular type I interferons, which have a powerful cytotoxic effect. This review examines the functioning of cytoplasmic nucleic acid sensors such as cGAS, STING, IFI16, AIM2, DAI, DDX41, DNA-PK, MRE-11, and TREX1 involved in activating the production of various cytokines.

Theranostic magnetic nanoparticles: Synthesis, properties, toxicity, and emerging trends for biomedical applications

Nanotechnology provides a wide range of nanosized devices, termed as nanotheranostics, that are integrated with diagnostic and therapeutic properties for real-time monitoring and treatment of diseases. In order to diagnose and cure diseases at the cellular and molecular level, the theranostic nanomedicine must first be able to circulate throughout the body without being destroyed by the host's immune system. Further, this can be linked to a biological ligand for targeting a specific organ or tissue. Novel non-invasive diagnostic agents, such as magnetic nanoparticles (MNPs), are currently employed in magnetic resonance imaging (MRI). Previously, they have been used for imaging various diseases; but new developments have unlocked the way for targeting the drug to the cellular membrane and multi-modal imaging with MNPs. For the production of MNPs, a wide range of synthetic methods such as physical and thermal degradation, hydrothermal production, microemulsion, co-precipitation, and polyol processes have been used, which include few examples of biosynthetic techniques. One of the biggest concern with MNPs is that they have potential toxicity issues in biomedical applications. Due to their reactive surface features and their capacity to penetrate the cell and tissue membranes, MNPs can elicit a powerful cytotoxic effect and hyperthermia. Numerous laboratories have studied in vitro cellular toxicity of MNPs in a wide variety of cancer and normal cell lines, and their findings established the fact that at low concentrations, MNPs are nontoxic, and at high concentrations, they have marginal toxicity, demonstrating their biocompatibility and acceptable safety profile. Diagnostic imaging using nanosystems can be performed using the aforementioned approaches, including MRI, optical imaging, nuclear imaging, computed tomography, ultrasound etc. In this article, various theranostic magnetic nanosystems are discussed in the context of their manufacturing and development for therapeutic and diagnostic use, focusing mainly on in vitro and in vivo applications. Further emphasis on their potential for integrating other nanostructures with current biotechnology, as well as the special qualities of magnetic nanosystems are further highlighted to explain the future role of magnetic nanosystems in the successful therapy.

Smart Nanofiber Mesh with Locally Sustained Drug Release Enabled Synergistic Combination Therapy for Glioblastoma.

This study aims to propose a new treatment model for glioblastoma (GBM). The combination of chemotherapy, molecular targeted therapy and radiotherapy has been achieved in a highly simultaneous manner through the application of a safe, non-toxic, locally sustained drug-releasing composite Nanofiber mesh (NFM). The NFM consisted of biodegradable poly(ε-caprolactone) with temozolomide (TMZ) and 17-allylamino-17-demethoxygeldanamycin (17AAG), which was used in radiation treatment. TMZ and 17AAG combination showed a synergistic cytotoxicity effect in the T98G cell model. TMZ and 17AAG induced a radiation-sensitization effect, respectively. The NFM containing 17AAG or TMZ, known as 17AAG-NFM and TMZ-NFM, enabled cumulative drug release of 34.1% and 39.7% within 35 days. Moreover, 17AAG+TMZ-NFM containing both drugs revealed a synergistic effect in relation to the NFM of a single agent. When combined with radiation, 17AAG+TMZ-NFM induced in an extremely powerful cytotoxic effect. These results confirmed the application of NFM can simultaneously allow multiple treatments to T98G cells. Each modality achieved a significant synergistic effect with the other, leading to a cascading amplification of the therapeutic effect. Due to the superior advantage of sustained drug release over a long period of time, NFM has the promise of clinically addressing the challenge of high recurrence of GBM post-operatively.

The Emerging Role of Tissue-Resident Memory CD8+ T Lymphocytes in Human Digestive Tract Cancers.

Malignant digestive tract tumors are a great threat to human public health. In addition to surgery, immunotherapy brings hope for the treatment of these tumors. Tissue-resident memory CD8+ T (Trm) cells are a focus of tumor immunology research and treatment due to their powerful cytotoxic effects, ability to directly kill epithelial-derived tumor cells, and overall impact on maintaining mucosal homeostasis and antitumor function in the digestive tract. They are a group of noncirculating immune cells expressing adhesion and migration molecules such as CD69, CD103, and CD49a that primarily reside on the barrier epithelium of nonlymphoid organs and respond rapidly to both viral and bacterial infection and tumorigenesis. This review highlights new research exploring the role of CD8+ Trm cells in a variety of digestive tract malignant tumors, including esophageal cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma. A summary of CD8+ Trm cell phenotypes and characteristics, tissue distribution, and antitumor functions in different tumor environments is provided, illustrating how these cells may be used in immunotherapies against digestive tract tumors.

CAR-NK Cells: From Natural Basis to Design for Kill.

Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been genetically modified. CAR-engineered T lymphocyte-based therapies have shown great success against blood cancers; however, potential fatal toxicity, such as in cytokine release syndrome, and high costs are some shortcomings that limit the clinical application of CAR-engineered T lymphocytes and remain to overcome. Natural killer (NK) cells are the focal point of current immunological research owing to their receptors that prove to be promising immunotherapeutic candidates for treating cancer. However, to date, manipulation of NK cells to treat malignancies has been moderately successful. Recent progress in the biology of NK cell receptors has greatly transformed our understanding of how NK cells recognize and kill tumor and infected cells. CAR-NK cells may serve as an alternative candidate for retargeting cancer because of their unique recognition mechanisms, powerful cytotoxic effects especially on cancer cells in both CAR-dependent and CAR-independent manners and clinical safety. Moreover, NK cells can serve as an ‘off-the-shelf product’ because NK cells from allogeneic sources can also be used in immunotherapies owing to their reduced risk of alloreactivity. Although ongoing fundamental research is in the beginning stages, this review provides an overview of recent developments implemented to design CAR constructs to stimulate NK activation and manipulate NK receptors for improving the efficiency of immunotherapy against cancer, summarizes the preclinical and clinical advances of CAR-NK cells against both hematological malignancies and solid tumors and confronts current challenges and obstacles of their applications. In addition, this review provides insights into prospective novel approaches that further enhance the efficiency of CAR-NK therapies and highlights potential questions that require to be addressed in the future.

Evaluating the effect of dermaseptin S4 and its derivatives on multidrug-resistant bacterial strains and on the colon cancer cell line SW620.

Dermaseptins are peptides found in the skin secretions of Phyllomedusinae frogs. These peptides exert a lytic action on various microorganisms and have no considerable hemolytic effect except dermaseptin S4 (DS4) which exhibits a powerful cytotoxic effect. Therefore, we synthesized several analogs of DS4 in an attempt to find molecules with a weak hemolytic effect and significant bioactivities. In this study, we performed the synthesis of truncated peptides by introducing C-terminal and N-terminal amino acid deletions of the native sequence. All peptide analogs, in comparison with parental peptide, were tested firstly on human red blood cells to work out their cytotoxicity, secondly on the multidrug-resistant bacteria by trying to find MICs, and finally on colon cancer tumor cell line SW620 using the MTT test so as to investigate the anti-proliferative effect. Our results showed that, on the one hand, the N terminus of the native peptide was necessary for the antibacterial activity and the anti-proliferative effect of the peptide. On the other hand, the hemolytic activity was more notable in the sequences broken down on the C-terminal side.

New Adenosine Derivatives from Aizoon canariense L.: In Vitro Anticholinesterase, Antimicrobial, and Cytotoxic Evaluation of Its Extracts.

Aizoaceae is a large succulent family characterized by many psychoactive species. Aizoon canariense L., a wild neglected plant traditionally used in gastrointestinal ailments, has been the subject of a limited number of phytochemical and biological studies. Therefore, herein, we investigated the in vitro cytotoxic, antimicrobial, and anticholinesteraseactivity of the aerial parts of A. canariense L. and analyzed the phytochemical compositions of the lipoidal and alkaloidal fractions. Petroleum ether extract showed the presence of behenic and tricosylic acid, while an in-depth investigation of the alkaloidal fraction revealed the identification of new adenine based alkaloids (1–5), which were isolated and identified for the first time from Aizoon canariense L. Their structures were elucidated based on extensive spectroscopic analyses. The alkaloidal extract showed a powerful cytotoxic effect (IC50 14–28 μg/mL), with the best effect against colon carcinoma, followed by liver and breast carcinomas. The alkaloidal extract also had a potent effect against Candida albicans and Escherichia coli, with minimum inhibitory concentrations (MIC) values of 312.5 and 625 µg/mL. The in vitro anticholinesterase activity was potent, with IC50 < 200 ng/mL for the tested extracts compared with 27.29 ± 0.49 ng/mL for tacrine.

Chimeric antigen receptor T cells engineered to secrete CD40 agonist antibodies enhance antitumor efficacy

BackgroundAlthough chimeric antigen receptor (CAR)-T cell therapy has been remarkably successful for haematological malignancies, its efficacy against solid tumors is limited. The combination of CAR-T cell therapy with immune checkpoint inhibitors (CPIs), such as PD-1, PD-L1, and CTLA-4 antibodies, is a promising strategy for enhancing the antitumor efficacy of CAR-T cells. However, because most patients acquire resistance to CPIs, investigating other strategies is necessary to further improve the antitumor efficacy of CAR-T cell therapy for solid tumors. Recently, CD40 agonist antibodies showed potential antitumor efficacy by activating the CD40 pathway.ResultsBased on the piggyBac transposon system, rather than the widely used viral vectors, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possessed the ability to secrete anti-CD40 antibodies. Compared with meso3 CAR-T cells, which did not secrete the anti-CD40 antibody, meso3-CD40 CAR-T cells secreted more cytokines and had a relatively higher proportion of central memory T (TCM) cells after stimulation by the target antigen. In addition, compared with meso3 CAR-T cells, meso3-CD40 CAR-T cells had a more powerful cytotoxic effect on target cells at a relatively low effector-to-target ratio. More importantly, we demonstrated that the antitumor activity of meso3-CD40 CAR-T cells was enhanced in a human ovarian cancer xenograft model in vivo.ConclusionsIn conclusion, these results highlight anti-CD40-secreting CAR-T cells generated by nonviral vectors as a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

RAAV9-UPII-TK-EGFP can precisely transduce a suicide gene and inhibit the growth of bladder tumors

ABSTRACT Bladder cancer is a common and widespread cancer of the human urinary system, and its incidence is increasing. Gene therapy is a promising treatment of bladder cancer. In our study, a recombinant adeno-associated virus (rAAV9-UPII-TK-EGFP) driven by a UPII promoter was constructed. The efficacy and safety of infection of bladder cells was tested in vivo and in vitro. The ability of rAAV9-UPII-TK-EGFP to penetrate the glycosaminoglycan (GAG) layer on the surface of bladder cells and to transduce the bladder cells in vivo was very high. Additionally, we confirmed that the TK/GCV system has a powerful cytotoxic effect on bladder tumor cells in vitro and in vivo. Thus, our data indicate that rAAV9-UPII-TK-EGFP is a precise gene drug delivery system for the treatment of bladder cancer, and the TK/GCV therapeutic strategy has a powerful antitumor effect. These findings can be widely used in clinical and scientific studies.

Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers.

An increasing number of artemisinin (ARS) and its derivatives have been reported for their potential therapeutic value of human cancer. However, their therapeutic potencies are limited owing to their poor pharmacokinetic profiles. Our previous studies showed that a lead compound ARS4 originated from incorporating the pharmacophore of the approved chemotherapeutic agent melphalan into the basic skeleton of artemisinin with a succinic linker exhibited an excellent toxicity to human ovarian cancer cells and low cytotoxicity to normal cells. The mechanism studies demonstrated that it inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis and inhibition of migration. Meanwhile, it exhibited excellent antitumor activities in animal models. Herein, further structure optimization for this lead compound ARS4 was performed and nineteen novel derivatives were designed and synthesized. Among them, compounds 10-12, 15, 16, 18 and 19 demonstrated powerful cytotoxic effects against human liver cancer and ovarian cancer cell lines, with their IC50s below 0.86μM against Hep3B and A2780cell lines, which are superior to that of ARS4. Four compounds (11, 15, 16 and 18) were selected to further evaluate their antitumor activities in invitro and invivo ovarian and liver cancer models, the results indicated that compound 18 exhibited the best therapeutic effect, not only effectively inhibited the growth of 7404 xenograft and Huh7 xenograft, but also presented a good dose-dependent inhibition toward the growth of A2780 xenograft. Overall, based on these positive results, these novel chemical structures may provide a new inspiration for the discovery of novel antitumor agents originated from artemisinin scaffolds.

Combination of Cytochalasin H and zinc oxide nanoparticles in human breast cancer: an insight into apoptosis study

Nanoparticle-mediated combination therapies have significant impact on improving the therapeutic efficacy of cancer. The aim of the current work was to investigate the apoptotic efficacy of Zinc Oxid nanoparticles (ZnONPs) in combination with Cytochalasin H (CytoH) in human MCF-7 breast cancer cells. The anti cancer activity of combined treatment of CytoH and ZnONPs was performed using MTT assay, Annexin V-propidium iodide staining, Caspase assay, and Hoechst 33342 staining. Quantitative real-time polymerase chain reaction was conducted to detect of p53 as a tumor suppressor gene expression in cancerous cells. Also, measurement of ROS generation was performed using flow cytometry. According to the MTT assay results, the combination of CytoH and ZnONPs significantly decreased the viability of cancer MCF-7 cells than either CytoH or ZnONPs alone as compared with normal HEK293 cells. The experiments, such as caspase 8 and 9 assay and Hoechst 33342 staining, showed that the combined treatment of CytoH and ZnONPs significantly increased the level of cell apoptosis pathway as compared with breast cancer cells treated with CytoH or ZnONPs alone. As demonstrated by annexin V/PI detection assay, the percentage of apoptotic MCF-7 cells was significantly increased, following combined treatment with CytoH and ZnONPs as compared with CytoH or ZnONPs alone. Moreover, by comparing the combination of CytoH and ZnONPs to CytoH and ZnONPs alone the ability of combined treatment to up-regulate p53 gene expression was observed. The results of the present study showed that combination of CytoH and ZnONPs could have a powerful synergistic cytotoxic effect on breast cancer cell line. Moreover, this is the first report indicating a new insight into how CytoH and ZnONPs can enhance apoptosis and cell growth in breast cancer cells.

Abstract 2402: Apoptosis induced by non-thermal atmospheric pressure bio-compatible soft jet plasma on brain tumor through p38/MAPK signaling pathways

Abstract Brain tumor is one of the most lethal forms of cancer to human beings, among which Glioblastoma astrocytoma is the most familiar and quickly progressing type of astrocytic brain tumor in adults with poor prognosis are still a therapeutic challenge. Current therapy options at diagnosis are multimodal and include surgical resection, radiation, and chemotherapy but difficulty to failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy and intrinsic resistance of tumor cells. Therefore new therapy is needed that can afford selective targeting of proliferating cells to promote current therapies. Non-thermal plasma can be considered as a potential cancer therapy for the alteration of biological and clinical applications by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS). In our study, we designate the effects of a NBP-J device to U87MG cell line. Previous research work established that jet plasma could induce apoptosis of various cancer cells, in particular indicative the selective cytotoxicity of cancer cells over normal cells. In this study, we assessed the effects of NBP-J on the U87MG brain cancer cell line including different effects and the physicochemical and biological correlation between the RONS cascade and p38/MAPK signaling pathway on the dose (time) dependent manner. The results of this study shows that the soft jet plasma significantly inhibits cell proliferation, inhibit survival pathway and induce apoptosis by p38/MAPK pathway in U87MG cells. The current results reveal that soft jet plasma has a powerful cytotoxic effect against brain cancer cells. Taken together, our results showed that NBP-J can become potential applications for effective and safe clinical trials for cancer therapy. Keywords: Non-thermal atmospheric-pressure plasma, soft jet plasma, Human glioblastoma, Cancer therapy. Acknowledgement This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF- 2016K1A4A3914113) funded by the Ministry of Science, ICT, and Future Planning (MSIP) of the Korean Government for EH. Choi, I. Han. Also this work was supported by the Basic Science Research Program through the Ministry of Science ICT of Korea (2019R1H1A2101686) for I. Han. Citation Format: Ihn Han. Apoptosis induced by non-thermal atmospheric pressure bio-compatible soft jet plasma on brain tumor through p38/MAPK signaling pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2402.

The biosynthesis of camptothecin derivatives by Camptotheca acuminata seedlings

10-hydroxycamptothecin and 9-methoxycamptothecin, naturally occurring camptothecin derivatives, are reportedly present in Camptotheca acuminata with a powerful cytotoxic effect and strong antitumor activity. In this paper, we studied the derivatization reaction of camptothecin catalyzed by C. acuminata seedlings. HPLC traced the reaction between exogenous camptothecin and C. acuminata seedlings. The results showed that the exogenous camptothecin was converted into 10-hydroxycamptothecin and 9-methoxycamptothecin by the tender roots and stems of C. acuminata seedlings, which would be a new method for the synthesis of two camptothecin derivatives.

Comprehensive anti-tumor effect of Brusatol through inhibition of cell viability and promotion of apoptosis caused by autophagy via the PI3K/Akt/mTOR pathway in hepatocellular carcinoma

Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial-mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan.

Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia.

Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.

Effective cytotoxic activity of OSW-1 on colon cancer by inducing apoptosis invitro and invivo.

As a natural compound, Ornithogalum caudatum Ait is primarily used as an anti-inflammatory and antitumor agent in Chinese folk medicine. In 1992, OSW-1 was isolated from this compound, which is a new member of cholestane saponin family. In numerous recent studies, OSW-1 has been shown to have powerful cytotoxic anticancer effects against various malignant cells. However, the therapeutic efficacy of OSW-1 on colon cancer and the underlying mechanism are not understood. To explore the mechanism underlying OSW-1 in antitumor therapy, a therapeutic function analysis of OSW-1 on colon cancer was performed invitro and invivo. It was shown that with low toxicity on normal colonic cells, OSW-1 suppresses colon cancer cells invitro and this inhibition was via the intrinsic apoptotic pathway, which increased cellular calcium, changed mitochondrial membrane potential, disrupted mitochondrial morphology, and led to the release of cytochromec and the activation of caspase-3. Furthermore, in a nude mouse model, OSW-1 had a powerful effect on suppressing colon tumor proliferation without significant side effects through the apoptosis pathway. Taken together, these results demonstrate that OSW-1 is a potential drug for colon cancer treatment.

Cytotoxic and apoptotic effects of the combination of palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine and curcumin on non small lung cancer cell lines

Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78–100μM) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39–50μM) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48h, compared to single use of each agent, only in H1299 cell line (combination index <1). Apoptosis was evident by annexin v staining positivity, increased caspase 3/7 activity and the presence of pyknotic nuclei. Pro-apoptotic genes of TNFRSF10A and HRK were found to be involved in apoptotic cell death. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of lung cancer due to its promising cytotoxic and apoptotic effect.

Shikonin induces apoptosis of lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling antagonized by p300

Shikonin derivatives exert powerful cytotoxic effects including induction of apoptosis. Here, we demonstrate the cytotoxic efficacy of shikonin in vivo in xenograft models, which did not affect body weight as well as its reduction of cell viability in vitro using several non-small cell lung cancer (NSCLC) cell lines. We found that inhibition of AKT by shikonin activated the forkhead box (FOX)O3a/early growth response protein (EGR)1 signaling cascade and enhanced the expression of the target gene Bim, leading to apoptosis in lung cancer cells. Overexpression of wild-type or a constitutively active mutant of FOXO3a enhanced shikonin-induced Bim expression. The NAD+-dependent histone deacetylase sirtuin (SIRT)1 amplified the pro-apoptotic effect by deacetylating FOXO3a, which induced EGR1 binding to the Bim promoter and activated Bim expression. Meanwhile, PI3K/AKT activity was enhanced, whereas that of FOXO3a was reduced and p300 was upregulated by treatment with a sublethal dose of shikonin. FOXO3a acetylation was enhanced by p300 overexpression, while shikonin-induced Bim expression was suppressed by p300 overexpression, which promoted cell survival. FOXO3a acetylation was increased by p300 overexpression and treatment with SIRT1 inhibitor, improving cell survival. In addition, shikonin-induced FOXO3a nuclear localization was blocked by AKT activation and SIRT1 inhibition, which blocked Bim expression and conferred resistance to the cytotoxic effects of shikonin. The EGR1 increase induced by shikonin was restored by pretreatment with SIRT1 inhibitor. These results suggest that shikonin induces apoptosis in some lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling, and that AKT and p300 negatively regulate this process via Bim upregulation.

Quality of life Evaluation in patients receiving Steroids (the QuESt tool): initial development in children and young people with acute lymphoblastic leukaemia

BackgroundThe powerful cytotoxic and immunomodulatory effects of corticosteroids are an important element of the success that has been achieved in the treatment of acute lymphoblastic leukaemia (ALL). In addition to...

Cytotoxic Effect of Turkish Propolis on Liver, Colon, Breast, Cervix and Prostate Cancer Cell Lines

Purpose: To investigate the total polyphenolic and flavonoid contents, antioxidant power and cytotoxic activity of ethanol extracts of Turkish propolis (EEP).Methods: The total polyphenolic and flavonoid contents of EEP were determined by spectrometric methods. Antioxidant power and cytotoxic activity of EEP were evaluated using ferric reducing antioxidant power (FRAP) and MTT assays, respectively.Results: The total polyphenolic and flavonoid contents, and FRAP value of EEP were 124.6 ± 1.5 mg gallic acid/g sample dry weight , 42.0 ± 0.8 mg quercetin/g sample dry weight and 311.0 ± 2.5 mg trolox/g sample dry weight, respectively. EEP exhibited powerful cytotoxic effects against the five human cancer cell lines. The highest cytotoxic activity of Turkish EEP was demonstrated on PC-3 cell line (IC50 = 20.7±3.4 μg/mL).Conclusion: The results demonstrate that EEP is a good source of antioxidant and a natural antitumor agent capable of reducing cancer cell proliferation.Keywords: Propolis, Polyphenols, Cytotoxic effect, Cancer cell lines, Antioxidant activity Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch),