Apoptosis-inducing Effects Research Articles

Preparation of oxypeucedanin-loaded PLGA-chitosan nanoparticles: Cytotoxicity, apoptosis induction, and anti-angiogenic effects

There are some serious side effects associated with cancer chemotherapy. The medical properties of oxypeucedanin, among a wide range of natural products, are being tested for minimizing off-target effects. The aim of this study was to prepare and characterize oxypeucedanin (OPD)-loaded poly(lactic-co-glycolic acid (PLGA) nanoparticles (NPs) surface-modified with chitosan (CS) (OPD-PLGA–CS–NP). The cytotoxic, apoptotic, and anti-angiogenesis properties of OPC-NP were then investigated in vitro. OPD-PLGA–CS–NPs showed cytotoxic effects against diverse cancer cell lines, while these effects were less pronounced in HFF normal cells. OPD-PLGA–CS–NPs were also shown to possess apoptotic properties as shown by flowcytometry, fulrecent microscopy and real-time PCR. The antioxidant effects of OPD-PLGA–CS–NPs also demonstrated through scavenging of DPPH and ABTS free radicals. Additionally, OPD-PLGA–CS–NPs were shown to have antiangiogenic properties by using CAM assays. It would be worthwhile to conduct further in vivo studies on animal-bearing tumor models to further demonstrate the properties and anticancer properties of the OPD-PLGA–CS–NPs.

Synthesis and Anticancer Activity of Ergosterol Peroxide Hybrids With Paclitaxel Side Chain Inducing Apoptosis in Human Hepatoma Carcinoma Cells

The antitumor activities of natural paclitaxel (PTX), semisynthetic docetaxel, and cabazitaxel are highly dependent on their C-13 side chains. Therefore, using natural ergosterol peroxide (EP, 1) as the lead compound, two EP-PTX hybrids (EP-A2 and EP-B2) were prepared and their antitumor activities were evaluated against 4 kinds of human MCF-7, HepG2, HCT-116, and A549 cell lines in vitro. The results showed that both EP-A2 and EP-B2 inhibited the growth of all four kinds of tested tumor cell lines. For paclitaxel-resistant MCF-7 cells, both EP-A2 and EP-B2 showed significant inhibitory activity with relatively low IC50 values (9.39 μM and 8.60 μM, respectively). In addition, EP-B2 inhibited the growth of the HepG2 cells (IC50 = 7.82 μM) more successfully than EP. Preliminary studies of the mechanism suggest that EP-B2 could arrest the G1 phase transition in HepG2 cells. In addition, EP-B2 showed an obvious apoptosis-inducing effect in HepG2 cells, as detected by the Annexin V/PI binding assay and the Western blot assay. Hybrid EP-B2 has the potential to become a novel antitumor drug through further study of the mechanism of action and its structural modifications.

Hispolon induces apoptosis in oral squamous cell carcinoma cells through JNK/HO-1 pathway activation.

Oral squamous cell carcinoma (OSCC) has a high recurrence rate and poor prognosis. Hispolon, a polyphenolic compound with antiviral, antioxidant, and anticancer activities, is a potential chemotherapy agent. However, few studies have investigated the anti-cancer mechanism of hispolon in oral cancer. This present study used the cell viability assay, clonogenic assay, fluorescent nuclear staining, and flow cytometry assay to analyse the apoptosis-inducing effects of hispolon in OSCC cells. After hispolon treatment, the apoptotic initiators, cleaved caspase-3, -8, and - 9, were upregulated, whereas the cellular inhibitor of apoptosis protein-1 (cIAP1) was downregulated. Furthermore, a proteome profile analysis using a human apoptosis array revealed the overexpression of heme oxygenase-1 (HO-1) by hispolon, which was determined to be involved in caspase-dependent apoptosis. Moreover, cotreatment with hispolon and mitogen-activated protein kinase (MAPK) inhibitors revealed that hispolon induces apoptosis in OSCC cells through activation of the c-Jun N-terminal kinase (JNK) pathway and not the extracellular signal-regulated kinase (ERK) or p38 pathway. These findings indicate that hispolon may exert an anticancer effect on oral cancer cells by upregulating HO-1 and inducing caspase-dependent apoptosis by activating the JNK pathway.

APX‑115A, a pan‑NADPH oxidase inhibitor, reduces the degree and incidence rate of dry eye in the STZ‑induced diabetic rat model.

Dye eye disease (DED) is a common ocular disorder in patients with diabetes. It has been reported that APX-115A, a pan-nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase inhibitor, has an apoptosis-inducing effect on Epstein-Barr virus-infected retinal epithelial cells, but its effects in DED are poorly understood. Therefore, a rat model of diabetes was used in the present study to investigate whether APX-115A has an impact on DED in diabetic rats. A diabetic model was established in male Sprague Dawley rats via the intraperitoneal injection of streptozotocin. The eyeballs of the rats were treated with a solution containing APX-115A or a saline control. Tear secretion was measured with the phenol red thread tear test, and the morphology of the eyeball and lacrimal gland tissues was determined using hematoxylin and eosin staining. In addition, localization of NAPDH oxidase 2 (NOX2) in the eyeball and lacrimal gland tissues was detected by immunohistochemistry. The APX-115A treatment had no effect on body weight, blood glucose level or the size of the lacrimal glands. However, morphological changes, namely intracellular vacuoles and acinar atrophy, were observed in the lacrimal glands of the diabetic rats, and APX-115A treatment attenuated these changes. Immunohistochemistry revealed that NOX2 expression was decreased in the lacrimal glands of the diabetic rats, and APX-115A treatment did not attenuate the reduction in NOX2. The corneas of the diabetic rats treated with APX-115A exhibited no change in thickness but had lower NOX2 expression levels compared with those of the control diabetic rats. APX-115A also increased tear secretion and ameliorated the histological changes associated with diabetes. Furthermore, the NOX2 expression levels in the corneas of the diabetic rats treated with APX-115A were restored to the levels observed in normal rats. These findings suggest that APX-115A has potential as a therapeutic agent for DED.

Synthesis and evaluation of sulfonamide derivatives targeting EGFR790M/L858R mutations and ALK rearrangement as anticancer agents

Fourteen new compounds bearing sulfonamide groups that target EGFRT790M/L858R mutations and ALK rearrangement were synthesized and evaluated as dual-target tumor inhibitors. The study on the anti-proliferation activity on cancer cells showed that the sulfonamide derivative with pyrimidine nucleus had much better activities compared with those with quinazoline nucleus. Among them, compound 19e exhibited excellent activity against H1975 cancer cell lines (EGFRT790M/L858R high express) and H2228 cells (ALK rearrangement) with the IC50 values of 0.0215 μM and 0.011 μM, respectively. The ALK and EGFR kinase inhibition assays also provided similar results. Genotype selectivity of EGFR on kinase and cell level, cytotoxicity towards human normal cell lines and cell morphology assay implied that 19e had acceptable selectivity and low toxicity. In addition, the inhibitory activity of 19e on H1975 and H2228 cells cloning and its apoptosis-inducing effect on the two cell lines were studied, and its inhibitory effect on the invasion and migration of tumor cells were also investigated. All the results show that 19e is worthy of further study.

Anticancer Activity of Bitter Melon-Derived Vesicles Extract against Breast Cancer.

Due to their low immunogenicity, high biocompatibility and ready availability in large quantities, plant-derived vesicles extracts have attracted considerable interest as a novel nanomaterial in tumor therapy. Bitter melon, a medicinal and edible plant, has been reported to exhibit excellent antitumor effects. It is well-documented that breast cancer gravely endangers women's health, and more effective therapeutic agents must be urgently explored. Therefore, we investigated whether bitter melon-derived vesicles extract (BMVE) has antitumor activity against breast cancer. Ultracentrifugation was used to isolate BMVE with a typical "cup-shaped" structure and an average size of approximately 147 nm from bitter melon juice. The experimental outcomes indicate that 4T1 breast cancer cells could efficiently internalize BMVE, which shows apparent anti-proliferative and migration-inhibiting effects. In addition, BMVE also possesses apoptosis-inducing effects on breast cancer cells, which were achieved by stimulating the production of reactive oxygen species (ROS) and disrupting mitochondrial function. Furthermore, BMVE could dramatically inhibit tumor growth in vivo with negligible adverse effects. In conclusion, BMVE exhibits a pronounced antitumor effect on 4T1 breast cancer cells, which has great potential for use in tumor therapy.

Cytotoxic Effects of Homeopathic Preparations on Human Tumor Cells In Vitro

Abstract: The aim of this work was to conduct an in vitro assessment of the possible cytotoxic effects of homeopathic drugs and consider possible mechanisms. Background: Homeopathy is still widely used as a complementary (alternative) medicine in different countries throughout the world. However, the method raises a lot of scientific debate about its effectiveness and mechanisms of action. This is especially true concerning the use of homeopathy in cancer treatment. Objective: This work aimed to comparatively assess the cytotoxic effect of homeopathic remedies on tumor cell cultures. Materials and Methods: We studied different dilutions of homeopathic medicines: Hydrastis, Conium and Carcinosinum. Cell lines of prostate cancer PC-3, breast cancer MDA-MB-231, and lymphoblastic leukemia Jurkat were used as model tumor objects. Standard colorimetric MTT test and cytometric analysis of cells were used here to assess the viability and parameters of apoptosis of cells. Results: Comparative assessment of the cytotoxic and apoptosis-inducing effects did not reveal significant differences in the viability of tumor cells in the groups exposed to homeopathic preparations among themselves and in comparison with the control group. The effects of the action of homeopathic remedies are shown only in the form of trends. Some possible mechanisms of the obtained results are considered. Conclusion: The results obtained in vitro indicated the absence of a direct cytotoxic effect in the studied homeopathic preparations. Despite the objective data, this does not allow us to make a final conclusion about the absence of antitumor activity of these drugs in vivo, since the possible or potential effects depend on the parameters of a living organism that are difficult to control and are often based only on hypothetical mechanisms. Some aspects of the action of homeopathy probably cannot be reproduced in vitro.

Reversal of Multidrug Resistance by Symmetrical Selenoesters in Colon Adenocarcinoma Cells.

Recently, selenium containing derivatives have attracted more attention in medicinal chemistry. In the present work, the anticancer activity of symmetrical selenoesters was investigated by studying the reversal of efflux pump-related and apoptosis resistance in sensitive and resistant human colon adenocarcinoma cells expressing the ABCB1 protein. The combined effect of the compounds with doxorubicin was demonstrated with a checkerboard assay. The ABCB1 inhibitory and the apoptosis-inducing effects of the derivatives were measured with flow cytometry. Whole transcriptome sequencing was carried out on Illumina platform upon the treatment of resistant cells with the most potent derivatives. One ketone and three methyl ester selenoesters showed synergistic or weak synergistic interaction with doxorubicin, respectively. Ketone selenoesters were the most potent ABCB1 inhibitors and apoptosis inducers. Nitrile selenoesters could induce moderate early and late apoptotic processes that could be explained by their ABCB1 modulating properties. The transcriptome analysis revealed that symmetrical selenoesters may influence the redox state of the cells and interfere with metastasis formation. It can be assumed that these symmetrical selenocompounds possess toxic, DNA-damaging effects due to the presence of two selenium atoms in the molecule, which may be augmented by the presence of symmetrical groups.

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists

BackgroundThe prognosis of B-cell acute lymphoblastic leukemia (B-ALL) has improved significantly with current first-line therapy, although the recurrence of B-ALL is still a problem. Toll-like receptor 9 (TLR9) agonists have shown good safety and efficiency as immune adjuvants. Apart from their immune regulatory effect, the direct effect of TLR9 agonists on cancer cells with TLR9 expression cannot be ignored. However, the direct effect of TLR9 agonists on B-ALL remains unknown.MethodsWe discussed the relationship between TLR9 expression and the clinical characteristics of B-ALL and explored whether CpG 685 exerts direct apoptotic effect on B-ALL without inhibiting normal B-cell function. By using western blot, co-immunoprecipitation, immunofluorescence co-localization, and chromatin immunoprecipitation, we explored the mechanism of the apoptosis-inducing effect of CpG 685 in treating B-ALL cells. By exploring the mechanism of CpG 685 on B-ALL, the predictive biomarkers of the efficacy of CpG 685 in treating B-ALL were explored. These efficiencies were also confirmed in mouse model as well as clinical samples.ResultsHigh expression of TLR9 in B-ALL patients showed good prognosis. C-MYC-induced BAX activation was the key to the effect of CpG oligodeoxynucleotides against B-ALL. C-MYC overexpression promoted P53 stabilization, enhanced Bcl-2 associated X-protein (BAX) activation, and mediated transcription of the BAX gene. Moreover, combination therapy using CpG 685 and imatinib, a BCR-ABL kinase inhibitor, could reverse resistance to CpG 685 or imatinib alone by promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation.ConclusionTLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. CpG 685 monotherapy might be applicable to Ph− B-ALL patients with C-MYC overexpression and without BAX deletion. CpG 685 may also serve as an effective combinational therapy against Ph+ B-ALL.

MiR-326 regulates cell proliferation and apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis.

The dysregulation of microRNAs plays a critical role in the development of rheumatoid arthritis (RA). This study aims to explore the functional significance of miR-326 in RA. TheRT-qPCR results showed that miR-326 was downregulated in synovial tissues of RA patients and RA fibroblast-like synoviocytes (RA-FLS). We found that miR-326 couldtarget and reduce the expression of inhibitor of DNA binding 1 (Id1). MTT assay and flow cytometry were conducted to explore the biological function of miR-326.Our datarevealed that the upregulation of miR-326suppressed cell proliferation and induced apoptosis in RA-FLS. Incollagen-induced arthritis mice,intraarticular injection of lentivirus carryingmiR-326overexpression vectors could reduce the arthritis score and attenuate synovial inflammation and cartilage destruction. We also found thatlong non-coding RNA-Ewing sarcoma-associated transcript 1 (lncRNA-EWSAT1) was significantly increased in RAsynovial tissues and RA-FLS. TheRNA immunoprecipitation and RNApull-down assay indicated thatlncRNA-EWSAT1 directly bound and negatively regulated the expression of miR-326.Knockdown of lncRNA-EWSAT1 could upregulatemiR-326 expression and attenuate its proliferation inhibition and apoptosis induction effect in RA-FLS. In conclusion,the lncRNA-EWSAT1/miR-326 axis might provide a novel therapeutic target in the treatment of RA.

ACE2-Inhibitory Effects of Bromelain and Ficin in Colon Cancer Cells.

Background and Objectives: Bromelain and ficin are aqueous extracts from fruits of Ananas comosus and Ficus carcia plants, used widely for medical applications. Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE, degrading Ang II to angiotensin 1-7 and decreasing the cellular concentration of Ang II. Materials and Methods: In this study, we investigated the ACE2-inhibitory, antiproliferative, and apoptosis-inducing effects of ficin and bromelain on caco-2 cells. Results: We found that bromelain and ficin significantly reduced the viability of human colon cancer cells with IC50 value concentrations of 8.8 and 4.2 mg/mL for bromelain after 24 and 48 h treatments, and 8.8 and 4.2 mg/mL for ficin after 24 and 48 h treatments, respectively. The apoptosis of the caco-2 cell line treated with bromelain was 81.04% and 56.70%, observed after 24 and 48 h. Total apoptotic proportions in caco-2 cells treated with ficin after 24 and 48 h were 83.7% and 73.0%. An amount of 1.6 mg/mL of bromelain and ficin treatments on caco-2 cells after 24 h revealed a higher decrease than that of other concentrations in the expression of ACE2 protein. Conclusions: In conclusion, bromelain and ficin can dose-dependently decrease the expression of ACE2 protein in caco-2 cells.

Genetic Interference of FGFR3 Impedes Invasion of Upper Tract Urothelial Carcinoma Cells by Alleviating RAS/MAPK Signal Activity.

Upper tract urothelial cancer (UTUC) is a less common disease in Western countries but has a high level of prevalence in Asian populations. Compared to bladder cancer, unique etiologic and genomic factors are involved in UTUC. Fibroblast growth factor receptor 3 (FGFR3) up-regulation has been proposed as a promising target for bladder cancer therapy. In this study, we aimed to profile the expression of FGFR3 in Asian and Caucasian UTUC tissues and to evaluate the in vitro therapeutic efficacy of small interference RNA (siRNA)-mediated FGFR3 silencing in UTUC treatment. The FGFR3 expression levels in renal pelvis tissues and microarray sections from Asian and Caucasian patients with UTUC, respectively, were measured via immunohistochemistry. The BFTC-909 and UM-UC-14 UTUC cell lines were used to examine the effects of FGFR3 silencing on proliferation, migration, epithelial-mesenchymal transition (EMT) marker expression, and signaling machinery. FGFR3 expression increased as the TNM stage increased in both Asian and Caucasian UTUC tumors, and no statistical difference was identified between the two groups. In vitro studies demonstrated that FGFR3 siRNA delivery significantly inhibited proliferation and migration and suppressed the expression of EMT markers and transcription factors in UTUC cells. Mechanistically, FGFR3 silencing alleviated the constitutive expression of RAS and the phosphorylation of MAPK signaling mediators, including ERK1/2 and JNK1/2. FGFR3 silencing elicited an apoptosis-inducing effect similar to that of FGFR inhibition. Conclusion: siRNA-targeted FGFR3 expression may impede the expansion and invasion of UTUC cells by alleviating the RAS/MAPK signaling pathway. The genetic interference of FGFR3 expression via siRNA in UTUC cells may constitute a useful therapeutic strategy.

Discovery of Novel 3,11-Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity.

Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

Comparative studies on in vitro antitumor activities and apoptosis-inducing effects of enantiomeric ruthenium(II) complexes.

On the basis of our previous comparative studies on the DNA binding of a pair of ruthenium(II) complex enantiomers, Δ-[Ru(bpy)2PBIP]2+ and Λ-[Ru(bpy)2PBIP]2+ {bpy = 2,2'-bipyridine, PBIP = 2-(4-bromophenyl)imidazo[4,5-f]1,10-phenanthroline}, in this study, their antitumor activities and mechanisms were further investigated comparatively. The cytotoxicity assay demonstrated that both the enantiomers exerted selective antiproliferative effects on cancer cell lines A2780 and PC3. Fluorescence localization experiments suggested that both the enantiomers effectively permeated the nucleus of HeLa cells and co-localized with DNA, resulting in their DNA damage and apoptosis. Flow cytometry experiments showed that the apoptosis was enhanced by increasing the concentration of each enantiomer. Western blotting analyses indicated that both extrinsic and intrinsic apoptosis pathways were activated by the two enantiomers. miRNA microarray analyses displayed that both the enantiomers up- and downregulated multiple miRNAs, some of which were predicted to be associated with carcinogenesis. The above experimental results also showed that the Δ-enantiomer exerted a more potent antitumor activity, a higher efficiency of entering cancer cells and a stronger apoptosis-inducing effect compared with the Λ-enantiomer. Combined with the previously published research results, experimental results from this study implied that the antitumor activity of a metal complex might have originated from the conformation change of DNA in tumor cells caused by the intercalation of the complex, that the antitumor mechanism of a metal complex could be related to its DNA-binding mode, and that the antitumor efficiency of a metal complex could result from its DNA-binding strength.

Renieramycin T Derivative DH_22 Induces p53-dependent Apoptosis in Lung Cancer Cells.

Targeting apoptotic pathways has been identified as a promising strategy for the treatment of lung cancer. We synthesized a new derivative of renieramycin T (RT), named DH_22, and examined its anticancer activities in human lung cancer cells. The RT derivative DH_22 was chemically modified from RT. The apoptosis-inducing effect was evaluated in A549 cells by annexin V-FITC/PI staining and nuclear staining assay (Hoechst/PI). In addition, the molecular pathway was analyzed by western blot analysis. In the cell viability and nuclear staining tests, DH_22 was discovered to be cytotoxic with an IC50 of 13.27 μM; it induced apoptosis of lung cancer cells. Regarding the mechanism, DH_22 contributed to the activation of p53-dependent apoptosis and decreased the cellular level of c-Myc. The p53-dependent mechanism was indicated by an increase in p53, an induction of the pro-apoptotic Bax protein, and a decrease in the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein. DH_22 has great potential for further development as a new anticancer drug.

Accessing Apoptosis Induction and Metastasis Inhibition Effect of Magnolol on Triple Negative Breast Cancer In Vitro.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that still requires improvement in treatment. Magnolol extract, derived from the bark of Magnolia officinalis, has traditionally been used in Asia to treat sleeping disorders and anxiety, and as an anti-inflammatory agent. Several reports have indicated that magnolol may have the potential to inhibit the progression of hepatocellular carcinoma and glioblastoma. However, the anti-tumor effect of magnolol on TNBC remains unknown. In this study, we used two TNBC cell lines, MDA-MB-231 and 4T1, to examine the cytotoxicity, apoptosis, and metastasis effects of magnolol. These were evaluated using MTT assay, flow cytometry, western blotting, and invasion/migration transwell assay, respectively. Magnolol significantly induced cytotoxicity and extrinsic/intrinsic apoptosis in both TNBC cell lines. It also decreased metastasis and associated protein expression in a dose-dependent manner. Furthermore, the anti-tumor effect was associated with the inactivation of the epidermal growth factor receptor (EGFR)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT3) signaling pathway. Magnolol may not only induce cell death in TNBC through apoptosis signaling activation but also by down-regulating EGFR/JAK/STAT3 signaling, which mediates TNBC progression.

Apoptosis-Inducing Effects of Short-Chain Fatty Acids-Rich Fermented Pistachio Milk in Human Colon Carcinoma Cells

Pistachio milk (PM), an extraction product of pistachio, is protein- and fat-dense food. Short-chain fatty acids (SCFAs) are known for inducing cytotoxicity and apoptosis in colon carcinoma cells. This study aimed to find an optimal combination of probiotics that can produce a higher amount of SCFAs in PM. In addition, the anti-cancer effect of fermented PM on human colon carcinoma cells (Caco-2) was determined. The combinations of probiotics were as follows: Streptococcus thermophilus + Lactobacillus bulgaricus (C); C + Lactobacillus acidophilus (C-La); C + Lactobacillus gasseri (C-Lg); C + Bifidobacterium bifidum (C-Bb). The results indicated that fermented PM was produced after a short fermentation time in all the probiotics combinations. C-Bb produced up to 1.5-fold more acetate than the other probiotics combinations did. A significant amount of cytotoxicity, i.e., 78, 56, and 29% cell viability was observed in Caco-2 cells by C-Bb-fermented PM at 1, 2.5 and 5%, respectively. C-Bb-fermented PM (5%) induced early and late apoptosis up to 6-fold. Additionally, Caco-2 cells treated with C-Bb-fermented PM significantly induced the downregulation of α-tubulin and the upregulation of cleaved caspase-3, as well as nuclear condensation and fragmentation. Our data suggest that fermented PM, which is rich in acetate, may have the potential as a functional food possessing anti-colon cancer properties.

Alantolactone inhibits oesophageal adenocarcinoma cells through nuclear factor erythroid 2-related factor 2-mediated reactive oxygen species increment.

Oesophageal adenocarcinoma (EAC) is a highly lethal cancer associated with a rapidly rising incidence and a poor prognosis. Alantolactone, a sesquiterpene lactone isolated from inula helenium, has anti-inflammatory, antimicrobial, neuroprotective activities, and anticancer properties. In the present study, the anticancer effects of alantolactone on the human EAC cells were investigated in vitro and in vivo. After treated with alantolactone, the cell viability of KYAE-1, KYAE-2, OE19, and OE33 cells reduced significantly compared with that of the control cells. Alantolactone induced apoptosis of the EAC cell lines by inhibiting the protein expression levels of nuclear factor erythroid2-related factor 2 (Nrf2). Furthermore, the apoptosis-inducing effect of alantolactone was enhanced by Nrf2 knockdown while reduced by overexpression of Nrf2. Antioxidant α-tocopherol and glutathione can protect EAC cell lines against alantolactone. A xenograft nude mice model showed that alantolactone can inhibit EAC growth in vivo. Alantolactone inhibits oesophageal adenocarcinoma cells through Nrf2-mediated reactive oxygen species (ROS) increment. Alantolactone maybe a potential therapeutical candidate for treating EAC.

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis.

A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4'py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4'py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4'py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4'py)-JA. In vitro anticancer activity showed that 22-(4'py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4'py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4'py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.

Taurine induces upregulation of p53 and Beclin1 and has antitumor effect in human nasopharyngeal carcinoma cells in vitro and in vivo

Taurine is an amino acid that has several physiological functions. Previously, we reported the apoptosis-inducing effect of taurine in human nasopharyngeal carcinoma (NPC) cells in vitro. However, the effect of taurine on NPC cell growth in vivo has not been elucidated. Autophagy plays an important role in cell metabolism and exhibits antitumor effects under certain conditions. In this study, we investigated the effects of taurine on apoptosis- and autophagy-related molecules in NPC cells in vitro and in vivo. In our in vitro study, NPC cells (HK1-EBV) were treated with taurine, and Western blot and immunocytochemical analyses revealed that taurine co-upregulated Beclin 1 and p53, with autophagy upregulation. In the in vivo study, we used a nude mouse model with subcutaneous xenografts of HK1-EBV cells. Once the tumors reached 2–3 mm in diameter, the mice were provided with distilled water (control group) or taurine dissolved in distilled water (taurine-treated group) ad libitum (day 1) and sacrificed on day 13. The volume and weight of the tumors were significantly lower in the taurine-treated group. Using immunohistochemistry (IHC), we confirmed that taurine treatment reduced the distinct cancer nest areas. IHC analyses also revealed that taurine promoted apoptosis, as evidenced by an increase in cleaved caspase-3, accompanied by upregulation of p53. Additionally, taurine increased LC3B and Beclin 1 expression, which are typical autophagy markers. The present study demonstrated taurine-mediated tumor growth suppression. Therefore, taurine may be a novel preventive strategy for NPC.