Apoptosis In Human Cancer Cells Research Articles

Novel Antineoplastic Inducers of Mitochondrial Apoptosis in Human Cancer Cells.

I propose a new strategy to suppress human cancer completely with two entirely new drug compounds exploiting cancer's Warburg effect characterized by a defective mitochondrial aerobic respiration, substituted by cytosolic aerobic fermentation/glycolysis of D-(+)-glucose into L-(+)-lactic acid. The two essentially new drugs, compound 1 [P(op)T(est)162] and compound 3 (PT167), represent new highly symmetric, four-bladed propeller-shaped polyammonium cations. The in vitro antineoplastic highly efficacious drug compound 3 represents a covalent combination of compound 1 and compound 2 (PT166). The intermediate drug compound 2 is an entirely new colchic(in)oid derivative synthesized from colchicine. Compound 2's structure was determined using X-ray crystallography. Compound 1 and compound 3 were active in vitro versus 60 human cancer cell lines of the National Cancer Institute (NCI) Developmental Therapeutics Program (DTP) 60-cancer cell testing. Compound 1 and compound 3 not only stop the growth of cancer cells to ±0% (cancerostatic effect) but completely kill nearly all 60 cancer cells to a level of almost -100% (tumoricidal effect). Compound 1 and compound 3 induce mitochondrial apoptosis (under cytochrome c release) in all cancer cells tested by (re)activating (in most cancers impaired) p53 function, which results in a decrease in cancer's dysregulated cyclin D1 and an induction of the cell cycle-halting cyclin-dependent kinase inhibitor p21Waf1/p21Cip1.

Abstract LB_B23: Magnetospirillum magneticum promotes iron competition and triggers apoptosis in human cancer cells

Abstract Bacteria are increasingly envisioned as living agents that can be administered to patients to carry out therapeutic actions. Interest has been growing over the past years in harnessing these microorganisms for cancer treatment as dynamic vectors with enhanced tumor-targeting properties. While bacterial traits, such as modulation of an immune response, local secretion of toxins, and proliferation in tumors have been well studied, less is known about bacteria as competitors for nutrients. We, therefore, investigated the use of magnetotactic bacteria as living iron chelators in the tumor microenvironment by studying the resulting competition for this vital nutrient, and by investigating the consequent metabolic effects in cancer cells. To do this, we first recreated a hypoxic environment by establishing an in vitro co-culture system consisting of the magnetotactic strain Magnetospirillum magneticum AMB-1 incubated under low-oxygen conditions with human cancer cells. We first quantified bacterial siderophore production and found it to be equivalent to a relevant concentration of deferoxamine (DFO), a potent drug used in iron chelation therapy. Further experiments then revealed an increased expression of transferrin receptor 1 (TfR1) on the cell surface and a significant decrease of viability in various cancer cell lines, indicating the bacteria’s ability to alter iron homeostasis. Metabolic effects exerted by AMB-1 were then further investigated. We demonstrated a lower rate of cellular proliferation correlating with a growing ratio of bacteria to cancer cells. Additional experiments also confirmed elevated apoptotic states and an enhanced activity level of executioner caspases in cancer cells, with an increasing number of AMB-1 in the culture. Lastly, the performed assays uncovered several apoptosis-related proteins that displayed altered levels when AMB-1 bacteria were added to the culture. Overall, our findings show the potential of magnetotactic bacteria to act as self-replicating iron-chelating agents that interfere with the iron homeostasis of cancer cells and decrease cancer cell viability. The presented data suggests involvement of triggered apoptotic signals that correlate with an increasing number of AMB-1 in the culture. This intrinsic capability of AMB-1 to induce apoptosis in breast cancer cells thus represents an encouraging strategy that could serve as an additional antineoplastic approach to reinforce current bacterial cancer therapies. Citation Format: Stefano Menghini, Matej Vizovišek, Ping Shu Ho, Jonathas Enders, Simone Schürle. Magnetospirillum magneticum promotes iron competition and triggers apoptosis in human cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B23.

New Bioactive Peptides from the Mediterranean Seagrass Posidonia oceanica (L.) Delile and Their Impact on Antimicrobial Activity and Apoptosis of Human Cancer Cells.

The demand for new molecules to counter bacterial resistance to antibiotics and tumor cell resistance is increasingly pressing. The Mediterranean seagrass Posidonia oceanica is considered a promising source of new bioactive molecules. Polypeptide-enriched fractions of rhizomes and green leaves of the seagrass were tested against Gram-positive (e.g., Staphylococcus aureus, Enterococcus faecalis) and Gram-negative bacteria (e.g., Pseudomonas aeruginosa, Escherichia coli), as well as towards the yeast Candida albicans. The aforementioned extracts showed indicative MIC values, ranging from 1.61 μg/mL to 7.5 μg/mL, against the selected pathogens. Peptide fractions were further analyzed through a high-resolution mass spectrometry and database search, which identified nine novel peptides. Some discovered peptides and their derivatives were chemically synthesized and tested in vitro. The assays identified two synthetic peptides, derived from green leaves and rhizomes of P. oceanica, which revealed interesting antibiofilm activity towards S. aureus, E. coli, and P. aeruginosa (BIC50 equal to 17.7 μg/mL and 70.7 μg/mL). In addition, the natural and derivative peptides were also tested for potential cytotoxic and apoptosis-promoting effects on HepG2 cells, derived from human hepatocellular carcinomas. One natural and two synthetic peptides were proven to be effective against the "in vitro" liver cancer cell model. These novel peptides could be considered a good chemical platform for developing potential therapeutics.

Elephant TP53-RETROGENE 9 induces transcription-independent apoptosis at the mitochondria

Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. Tid1 expression is required for p53-R9-induced apoptosis. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers.

Thimerosal, a competitive thioredoxin reductase 1 (TrxR1) inhibitor discovered via high-throughput screening

Thioredoxin reductase 1 (TrxR1) is considered as an important anti-cancer drug target, inhibition of which can induce reactive oxygen species (ROS)-mediated apoptosis of human cancer cells. Here, we developed and optimized a high-throughput screening (HTS) assay based on enzyme kinetics for the discovery of TrxR1 inhibitors. By utilizing this assay, we performed a HTS for 2500 compounds from an in-house library against TrxR1. We found that a vaccine preservative, thimerosal, strongly inhibited TrxR1 in a competitive and reversible manner with an IC50 of 24.08 ± 0.86 nM. In addition, we determined that thiomersal has an inhibitory effect on the proliferation of A549 lung cancer cell line, with a GI50 of 6.81 ± 0.09 μM, slightly more potent than auranofin (GI50 = 11.85 ± 0.56 μM). Furthermore, we showed by flow cytometer that thimerosal effectively increased the content of ROS in A549 cells. Therefore, our work provided a high-throughput screening assay to quickly and effectively discover TrxR1 inhibitors, identifying thiomersal as a novel TrxR1 inhibitor and chemical probe.

Inactivation of Mad2B Enhances Apoptosis in Human Cervical Cancer Cell Line upon Cisplatin-Induced DNA Damage.

Mad2B (Mad2L2), the human homolog of the yeast Rev7 protein, is a regulatory subunit of DNA polymerase ζ that shares sequence similarity with the mitotic checkpoint protein Mad2A. Previous studies on Mad2B have concluded that it is a mitotic checkpoint protein that functions by inhibiting the anaphase-promoting complex/cyclosome (APC/C). Here, we demonstrate that Mad2B is activated in response to cisplatin-induced DNA damage. Mad2B co-localizes at nuclear foci with DNA damage markers, such as proliferating cell nuclear antigen and gamma histone H2AX (γ-H2AX), following cisplatin-induced DNA damage. However, unlike Mad2A, the binding of Mad2B to Cdc20 does not inhibit the activity of APC/C in vitro. In contrast to Mad2A, Mad2B does not localize to kinetochores or binds to Cdc20 in spindle assembly checkpoint-activated cells. Loss of the Mad2B protein leads to damaged nuclei following cisplatin-induced DNA damage. Mad2B/Rev7 depletion causes the accumulation of damaged nuclei, thereby accelerating apoptosis in human cancer cells in response to cisplatin-induced DNA damage. Therefore, our results suggest that Mad2B may be a critical modulator of DNA damage response.

Design, Synthesis, Docking Studies and Biological Evaluation of Novel Benzochromenopyrimidines via Silica Sulfuric Acid Catalyzed Reaction on Apoptosis in Human Cancer Cells

Via one-pot reaction of 2-naphthol, thiobarbituric acid and aldehyde in the presence of silica sulfuric acid (SSA) as a catalyst to synthesis benzochromenopyrimidines derivatives. Then we studied the reaction of benzochromenopyrimidines derivatives with bromoacetic acid to obtain benzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidine-11,13(10H,14H)-dione derivatives. Meanwhile, dichloroethane was reacted with 12-(4-fluorophenyl)-9-thioxo-9,10-dihydro-8H-benzo[5,6]chromeno[2,3-d]pyrimidin-11(12H)-one to form 14-(4-fluorophenyl)-10,11-dihydrobenzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidin-13(14H)-one. All new products structure was elucidated based on analytical and spectroscopic analyses. Anti-cancer activity of newly synthesized structures was investigated. Cancer cells (MDA-MB-231 and HepG2) were used to evaluate the anti-cancer activity of tested compounds using neutral red uptake assay. Treatment of MDA-MB-231 and HepG2 cells with tested compound 6h revealed more inhibitory influence after 48 h. The expression levels of BCL2, BAX, Caspase3, Survivin and P53 genes were investigated using QRT-PCR. This study exhibited that compound 6h revealed significant pro-apoptotic effect via down regulation of BCL2 and Survivin genes and up-regulation of BAX, Caspase3 and P53 genes when treated with MDA-MB-231 and HepG2 cells as compared to control values. The biological studies of these compounds were proved through molecular docking studies with human cyclin-dependent kinase 2 (PDB code: 2A4L) and compound 6h showed low binding energy and shortage bond length with different amino acids. Noteworthy, the tested compound 6h exhibited the most pronounced effect in this respect.

Retraction statement: The PI3K/AKT axis modulates AATF activity in Wilms' tumor cells.

FEBS Open BioVolume 12, Issue 12 p. 2262-2262 Retraction NoticeOpen Access Retraction statement: The PI3K/AKT axis modulates AATF activity in Wilms' tumor cells This article retracts the following: Retracted: The PI3K/AKT axis modulates AATF activity in Wilms’ tumor cells Peng Jing, Jiaqiong Zou, Kegui Weng, Pei Peng, Volume 8Issue 10FEBS Open Bio pages: 1615-1623 First Published online: September 4, 2018 First published: 15 November 2022 https://doi.org/10.1002/2211-5463.13514AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat https://doi.org/10.1002/2211-5463.12500 The above article published online on 04 August 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the Editor-in-Chief, John Wiley and Sons Ltd and the authors. The retraction has been agreed following an investigation based on allegations raised by a third party, which revealed that some images in this article are inappropriate duplications of images from a previously published article [[1]]. Thus, the editors consider the conclusions of this manuscript substantially compromised. Reference 1Lee YJ, Cui J, Lee J, Han A-R, Lee EB, Jang HH, et al. Cytotoxic Compounds from Juglans sinensis Dode Display Anti-Proliferative Activity by Inducing Apoptosis in Human Cancer Cells. Molecules. 2016; 21: 120. https://doi.org/10.3390/molecules21010120 Volume12, Issue12December 2022Pages 2262-2262 ReferencesRelatedInformation

Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions.

Turmeric spice contains curcuminoids, which are polyphenolic compounds found in the Curcuma longa plant's rhizome. This class of molecules includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Using prostate cancer cell lines PC3, LNCaP, DU145, and C42B, we show that curcuminoids inhibit cell proliferation (measured by MTT assay) and induce apoptosis-like cell death (measured by DNA/histone ELISA). A copper chelator (neocuproine) and reactive oxygen species scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide) significantly inhibit this reaction, thus demonstrating that intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitize normal breast epithelial cells (MCF-10A) to curcumin-mediated growth inhibition, as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters CTR1 and ATP7A in MCF-10A cells, which is attenuated by the addition of curcumin in the medium. We propose that the copper-mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of curcuminoids.

Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity

Targeting endoplasmic reticulum (ER) stress presents a promising strategy in cancer therapy. We previously reported a series of 1,2,4-oxadiazole derivatives that induced the degradation of EGFR and c-Met which are implicated in tumorigenesis. Based on our previous SAR studies, herein, we report the discovery of EMD37, a novel 1,2,4-oxadiazole derivative, which demonstrated potent anticancer activity against NCI-60 cancer cell lines panel compared to its parent/lead compounds. Anti-proliferative assays revealed preferential cytotoxicity of EMD37 on cancer cells compared to normal cells. Delving deeper, we exploited unbiased genome-wide transcriptome profiling of EMD37-treated cancer cells. Gene Ontology and gene set enrichment analyses revealed that EMD37 promoted ER stress and unfolded protein response (UPR) machinery which was confirmed using RT-qPCR. Mining drug signature databases also confirmed the enrichment of the signature of canonical UPR inducers. Knocking down ER stress transcription factors compromised at least partly the anticancer activity of EMD37. Immunoblot analysis showed that EMD37 induced the accumulation of polyubiquitinated proteins and inhibited mTOR signaling. EMD37 induced G2/M cell cycle arrest and apoptosis of human cancer cells. Inhibiting apoptosis evidently abrogated the anticancer efficacy of EMD37. Altogether, this study introduces EMD37 as a novel ER inducer which warrants further investigation as a potentially relevant anti-cancer therapy.

Fractions of Hoslundia opposita Vahl and hoslundin induced apoptosis in human cancer cells via mitochondrial-dependent reactive oxygen species (ROS) generation

BackgroundCancer remains one of the leading causalities of several morbidity and mortality with negative impact on global economy due to low workforce and management/treatment cost. A number of conventional therapies have been explored in the management/treatment of cancer including chemotherapeutic intervention, radiotherapy, and surgery. Among these treatment modalities, chemotherapy remains the most popular first line of intervention in management/treatment of cancer, and natural products have been implicated as the main source of antineoplastic agents with phenomenal efficacy. However, current antineoplastic agents suffer from lack of selectivity and specificity necessitating the need for further research in the search for novel anticancer drug molecules. MethodsIn this present study, the anticancer activity of Hoslundia opposita leaves extracts were tested against a number of cell lines including human hepatoma cell line (HepG2), human breast cancer cell lines (MDA-MB-231), intestinal epithelial cell lines (Caco-2), and human keratinocyte HACAT cell lines. A bio-guided fractionation assay and the structural elucidation of the pure isolate (hoslundin) was conducted by 1D and 2D NMR spectroscopy. The cell viability, colony formation, and apoptotic activities were investigated using MTT assay, clonogenic assay, and caspase − 3 and − 7 kits respectively. Flow cytometry was employed in assessing the altered cell cycle expression. The production of the intracellular reactive oxygen species (ROS) levels and the reduction of the mitochondrial membrane potential (MMP) was determined at the cellular level using fluorescent probe dyes dihydro-fluorescin diacetate (DCFH-DA) and tetramethylrhodamin (TMRE), respectively. ResultsThe H. opposita fractions and its pure isolate (hoslundin) demonstrated a potent cytocidal activity against the tumorigenic cells (HepG2, MDA-MB-231, Caco-2) at concentration ranging from 25 to 100 µg/mL. The inhibition of the colony formation was significantly observed in HepG2 cell lines. More so, the cellular viability of the normal cells (HaCaT) was relatively unchanged in the presence of H. opposita fractions and its isolate proving the selectivity of the compounds towards tumourigenic cells. The H. opposita fractions and hoslundin exerted their anticancer activity via cell cycle arrest with the accumulation of the DNA content at the S-phase, activation of apoptosis in the caspase 3,7 activities and depolarized mitochondrial membrane potential mediated by mitochondrial-dependent ROS generation in the treated tumor cells. ConclusionThe anticancer activities of Hoslundia opposita Vahl and hoslundin exhibited significant efficacy against tumor cells and well tolerated in the presence of normal cells making them a potential antineoplastic agent.

Curcuma aeruginosa Roxb. exhibits cytotoxicity in A-549 and HeLa cells by inducing apoptosis through caspase-dependent pathways.

The aim of the current study was to examine the efficacy of the leaf, stem and rhizome ofCurcuma aeruginosa Roxb. for their phytochemical content, antioxidant and anti-cancer activities. The different parts of C. aeruginosa were subjected to sequential extraction to give three fractions viz., hexane, ethyl acetate and methanol extract. The cytotoxic effectand the mode of action against A-549 humanlung adenocarcinoma and HeLa celllines were examined. C. aeruginosa presented no significant toxic effect in normal human lung cells (L-132). The methanol extracts were found to be the most cytotoxic and further investigation was carried out to understand the effects. The methanol extracts induced DNA damage after 24h with significant increase in tail DNA and tail moment when compared to untreated control. Up-regulation in the expression of thecaspase -8 and -3activity was observed after 48h of treatment. The mechanism of cell death and apoptosis induced by the methanol extracts on A549 and HeLa cells were studied using fluorescent staining. Bioactive compounds detected from the HPLC revealed phenol and flavonoid compounds: Gallic acid, quercetin, caffeic acid, kaempferol, rutin, coumaric acid and naringenin. GC-MS results identified the presence of sesquiterpenoids: α-curcumene, curzerene curcumenol, curzerenone epicurzerenone, caryophyllene oxide and diterpenoid, andrographolide. These compounds are known for inducing apoptosis in human cancer cells through caspase - dependent pathways. Therefore, C. aeruginosa and its potential to induce apoptosis in cancer cells suggest that they have potential in medical applications.

Mononuclear cobalt(II) complexes with polypyridyl ligands: Synthesis, characterization, DNA interactions and in vitro cytotoxicity towards human cancer cells

Mononuclear cobalt(II) complexes [CoII(L1)Cl2]; 1, [CoII(L1)(bpy)Cl]PF6; 2, [CoII(L1)(phen)Cl]PF6; 3 and [CoII(L2)Cl2]; 4 (where L1 = N,N-bis(pyridin-2-ylmethyl)aniline, L2 = (2,4,6-trimethyl-N,N-bis(pyridin-2-ylmethyl)aniline, bpy = 2,2/−bipyridine, phen = 1,10-phenanthroline) were synthesized and characterized by different analytical and spectroscopic methods. All the complexes were structurally identified by single-crystal X-ray crystallography. Penta-coordinated complex 1 adopted distorted trigonal bipyramidal and hexacoordinated complexes 2 and 3 having distorted octahedral geometry whereas tetra-coordinated complex 4 has distorted tetrahedral geometry. The interactions of salmon sperm DNA (ss-DNA) with complexes (1-4) were investigated by absorbance, fluorescence spectroscopy and molecular docking studies. All the complexes are very susceptible to DNA binding and the binding affinity (Kb) follows the order 3 (2.05 × 104 M −1) > 4 (1.40 × 104 M −1) > 2 (1.36 × 104 M −1) > 1 (1.34 × 104 M −1) indicating they have superior DNA binding ability. The Stern-Volmer constant (Ksv) ranges from 1.10 × 104 M −1 to 1.95 × 104 M −1 suggesting weak or moderate binding with DNA. DNA cleavage study in plasmid DNA reveals very efficient DNA cleavage factors even in the absence of any external agents. Using multiple biochemical assays, we have demonstrated that 1–4 induces apoptosis of human cancer cells with IC50 values of 26.48 ± 1.45 μM, 10.89 ± 0.55 μM, 7.63 ± 0.4 μM and 37.67 ± 2.06 μM, respectively in A549 lung adenocarcinoma cells and 14.45 ± 0.73 μM, 1.97 ± 0.1 μM, 0.98 ± 0.05 μM and 24.43 ± 1.22 μM, respectively in MDA-MB-231 breast adenocarcinoma cells.

Upregulation of BAX and caspase-3, as well as downregulation of Bcl-2 during treatment with indeno[1,2-b]quinoxalin derivatives, mediated apoptosis in human cancer cells.

Cancer is the world's foremost cause of death. There are over 100 different forms of cancer. Cancers are frequently named after the organs or tissues in which they develop. As a part of our aim to develop promising anticancer agents, a series of new indeno[1,2-b]quinoxaline derivatives were synthesized. All of the synthesized compounds were tested for anticancer activity in vitro in three human cancer cell lines: the HCT-116 colon cancer cell line, the HepG-2 liver cancer cell line, and the MCF-7 breast cancer cell line. Among the tested derivatives, 2, 3, 5, 12, 21, and 22 showed exceptional antiproliferative activities against the three tested cell lines compared to the reference standard imatinib. These compounds were, therefore, selected for further investigations. Evaluation of their cytotoxicity against a normal human cell line (WI-38) was performed, to ensure their safety and selectivity (IC50 > 92 μM). Then, induction of apoptosis by the most active compounds was found to be accomplished by downregulation of Bcl-2 and upregulation of BAX and caspase-3. After that, the most promising apoptotic compound that increases the caspase-3 and BAX expression and downregulates Bcl-2 activity (3) was assessed for its impact on the cell cycle distribution in HepG-2 cells: The most potent derivative (3) induced cell cycle arrest at the G2/M phase. Finally, in silico evaluation of the ADME properties indicated that compound 3 is orally bioavailable and can be readily synthesized on a large scale.

Draft genome sequence of the cyanobacterium Sphaerospermopsis aphanizomenoides BCCUSP55 from the Brazilian semiarid region reveals potential for anti-cancer applications.

Sphaerospermopsis aphanizomenoides is a filamentous nitrogen-fixing and bloom-forming cyanobacterium, which biomass can fertilize natural water with nutrients, especially through nitrogen fixation. The Sphaerospermopsis aphanizomenoides strain BCCUSP55 was previously isolated from a water supply reservoir in the Brazilian semiarid region, and its draft genome assembly coupled with the gene contents are reported here. The obtained BCCUSP55 draft genome comprised 254 scaffolds with a genome size estimated of 6,096,273bp. In addition, it has 5250 predicted coding sequences (CDS) and the G + C content is 38.5%. Further, the BCCUSP55 draft genome presented the putative nocuolin A gene complete cluster, a natural oxadiazine that triggers apoptosis in human cancer cells. Thus, our results contribute to extend the knowledge on the genus Sphaerospermopsis and reveal its biotechnological potential.

Kahweol Induces Apoptosis in Hepatocellular Carcinoma Cells by Inhibiting the Src/mTOR/STAT3 Signaling Pathway.

Kahweol, a coffee-specific diterpene, induces apoptosis in human cancer cells, and some targets of kahweol-mediated apoptosis have been identified. However, the specific apoptotic effects and mechanism of action of kahweol in hepatocellular carcinoma (HCC) cells are unknown. This study was performed to investigate the molecular mechanism by which kahweol induces apoptosis in HCC cells. The Src pathway is associated with apoptosis in cancer. In this study, we found that kahweol induces apoptosis by inhibiting phosphorylation of Src, and also inhibiting p-mTOR and p-STAT3. Therefore, we suggest that kahweol is a potent inhibitor of HCC cell growth.

Betulinic acid induces autophagy-dependent apoptosis via Bmi-1/ROS/AMPK-mTOR-ULK1 axis in human bladder cancer cells.

Betulinic acid (BA), a pentacyclic triterpenoid isolated from tree bark, exhibits antitumor effects against solid malignancies and triggers autophagy and/or apoptosis in human cancer cells. Nonetheless, the relationship between autophagy and apoptosis and the potential modulatory actions of BA on autophagy-dependent bladder cancer cell death remain unclear. The present study showed that BA exposure significantly suppressed viability, proliferation, and migration of EJ and T24 human bladder cancer cells. These effects reflected caspase 3-mediated apoptosis and could be attenuated or abolished by inhibiting ROS production with N-acetyl-L-cysteine, inhibiting autophagy with chloroquine, or silencing ATG7 with targeted siRNA. BA-induced autophagy was evidenced by epifluorescence imaging of lentivirus-induced expression of mCherry-GFP-LC3B and increased expression of two autophagy-related proteins, LC3B-II and TEM. Moreover, enhanced AMPK phosphorylation and decreased mTOR and ULK-1 phosphorylation suggested BA activates autophagy via the AMPK/mTOR/ULK1 pathway. Accordingly, exposure to dorsomorphin (Compound C), an AMPK inhibitor, and AICAR, an AMPK activator, respectively inhibited and stimulated BA-induced autophagy in EJ and T24 cells. The effects of Bmi-1 overexpression in vitro and decreased Bmi-1 expression in BA-treated T24 cell xenografts in nude mice suggested that downregulation of Bmi-1 is the underlying mechanism in BA-mediated, autophagy-dependent apoptosis.

A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo.

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

11]-Chaetoglobosins from Pseudeurotium bakeri Induce G2/M Cell Cycle Arrest and Apoptosis in Human Cancer Cells.

Twelve new [11]-chaetoglobosins, chaetopseudeurins A-L (1-12), were identified from the fermentation of the endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Compounds 2 and 5-7 exhibited significant cytotoxicities against seven human cancer cell lines, with IC50 values ranging from 4.7 ± 1.0 to 12.2 ± 0.7 μM, and induced G2/M cell cycle arrest and apoptosis in MCF-7 and A427 cells dose dependently. Western blot analysis showed that compound 2 induced apoptosis of MCF-7 cells via the Bcl-2/caspase-3/PARP pathway.

Viral Proteins as Emerging Cancer Therapeutics.

Simple SummaryThis review is focused on enlisting viral proteins from different host sources, irrespective of their origin, that may act as future cancer curatives. Unlike the viral proteins that are responsible for tumor progression, these newly emerged viral proteins function as tumor suppressors. Their ability to regulate various cell signaling mechanisms specifically in cancer cells makes them interesting candidates to explore their use in cancer therapy. The discussion about such viral components may provide new insights into cancer treatment in the absence of any adverse effects to normal cells. The study also highlights avian viral proteins as a substitute to human oncolytic viruses for their ability to evade pre-existing immunity.Viruses are obligatory intracellular parasites that originated millions of years ago. Viral elements cover almost half of the human genome sequence and have evolved as genetic blueprints in humans. They have existed as endosymbionts as they are largely dependent on host cell metabolism. Viral proteins are known to regulate different mechanisms in the host cells by hijacking cellular metabolism to benefit viral replication. Amicable viral proteins, on the other hand, from several viruses can participate in mediating growth retardation of cancer cells based on genetic abnormalities while sparing normal cells. These proteins exert discreet yet converging pathways to regulate events like cell cycle and apoptosis in human cancer cells. This property of viral proteins could be harnessed for their use in cancer therapy. In this review, we discuss viral proteins from different sources as potential anticancer therapeutics.