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Apoptosis and Cancer

"One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; ( DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth." (Source: MeSH)

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Latest Research Publications

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Chaouki W, Meddah B, Hmamouchi M
Antiproliferative and apoptotic potential of Daphne gnidium L. root extract on lung cancer and hepatoma cells.
Pharmazie. 2015; 70(3):205-10 [PubMed] Related Publications
Daphne gnidium L. (Thymeleacees) is a famous Moroccan plant with cancer-related ethnobotanical use. Previously, we demonstrated that ethyl acetate extract of D. gnidium had antiproliferative and pro-apoptotic potential on human breast tumor MCF-7 cells. The purpose of this study was to investigate if the antiproliferative effect of this extract was similar for different human cancer cell lines such as A549 lung cancer and SMMC-7721 hepatoma cells. Moreover, this work essentially focused on the intrinsic apoptotic signaling pathway. Antiproliferative activity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide on A549 and SMMC-7721 cells. The characterization of the mechanisms involved in this effect was determined by lactate dehydrogenase test, apoptosis assays and western blot analyses. Our present study has shown that this extract strongly inhibited proliferation of A549 (IC50: 213 ± 15 μg/ml) and SMMC-7721 (IC50: 170 ± 13 μLg/ml) cells. The characterization of antiproliferative effect demonstrated that this extract was an apoptosis inducer in both cell lines tested. The results of western blot analyses have shown in SMMC-7721 cells that this extract activated caspase signaling triggered by the modulation of Bcl-2 family proteins. These findings suggest that this natural extract-induced effects may have novel therapeutic applications for the treatment of different cancer types.

Yuan Y, Zhang X, Zeng X, et al.
Glutathione-mediated release of functional miR-122 from gold nanoparticles for targeted induction of apoptosis in cancer treatment.
J Nanosci Nanotechnol. 2014; 14(8):5620-7 [PubMed] Related Publications
MiRs was efficiently bound to water-soluble positively charged gold nanoparticles through complementary electrostatic interaction. MiR-122 has been considered to be specifically expressed in liver and involved in inducing hepatocyte apoptosis through bcl-w pathway, which could be efficiently bound to water dispersible positively charged gold nanoparticles and conjugated with folic acid (FA) to target specific cancer cells, through complementary electrostatic interaction. These gold nanoparticles-miR-122-FA nanocomplexes (GMN) were disrupted and miR-122 was released by glutathione (GSH) at intracellular concentrations. In contrast, there was almost no detectable miR-122 released from GMN by extracellular concentration of GSH. The formation of GMN and GSH-mediated miR-122 release from the complexes were corroborated by dye displacement assay, electrophoresis experiment and transmission electron microscopy (TEM). With FA funcition, the GMN can target to the HepG2 cell membrane efficiently revealed by scanning electron microscopy (SEM). The released miR-122 retained apoptosis-inducing activity after being transfected into HepG2 cells. The transfection efficiency measured by MTT assay and flow cytometry was comparable with the positive control. We determined the effects of GMN on HepG2 cells viability and apoptosis by using fluorescence light microscopy and SDS-PAGE/immunoblots. The obvious concentration gradient of GSH in nature between the intra- and extracellular environments as well as the GSH concentration-dependent release suggest that these positively charged gold nanoparticles can be used as a novel visible vehicle for gene delivery and open up promising opportunities for target applications in the future.

Xia D
Ovarian cancer HO-8910 cell apoptosis induced by crocin in vitro.
Nat Prod Commun. 2015; 10(2):249-52 [PubMed] Related Publications
The effect and mechanism of ovarian cancer HO-8910 cell apoptosis induced by crocin.MTT assay was performed to detect the inhibitory action of crocin on the proliferation of HO-8910 cells. Flow cytometry was used to test the cell cycle distribution and apoptosis rate of ovarian cancer HO-8910 cells. Western blot analysis was utilized to measure the levels of apoptotic proteins such as p53, Fas/APO-1, and Caspase-3. MTT analysis revealed that crocin significantly inhibited the growth of HO-8910 cells. Additionally, flow cytometry illustrated that crocin raised the proportion of HO-8910 cells in the G0/G1 phase and increased their apoptosis rate. Furthermore, Western blot analysis revealed that crocin up-regulated the expression of p53, Fas/APO-1, and Caspase-3. The results of this study showed that crocin can significantly inhibit the growth of HO-8910 cells and arrest them in the G0/G1 phase. Crocin can also promote ovarian cancer HO-8910 cell apoptosis, most likely by increasing p53 and Fas/APO-1 expression, and then activating the apoptotic pathway regulated by Caspase-3.

Rahman HS, Rasedee A, Chartrand MS, et al.
Zerumbone induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in Jurkat cell line.
Nat Prod Commun. 2014; 9(9):1237-42 [PubMed] Related Publications
This investigation determined the anticancer properties of zerumbone (ZER) on the human T-cell (Jurkat) line using the MTT assay, microscopic evaluations, flow cytometric analyses, and caspase activity estimations. The results showed that ZER is selectively cytotoxic to Jurkat cells in a dose and time-dependent manner with IC50 of 11.9 ± 0.2, 8.6 ± 0.5 and 5.4 ± 0.4 μg/mL at 24, 48 and 72 hours of treatment, respectively. ZER did not produce an adverse effect on normal human peripheral blood mononuclear cells (PBMC). ZER is not as cytotoxic as doxorubicin, which imposed an inhibitory effect on Jurkat cells with IC50 of 2.1 ± 0.2, 1.8 ± 0.15, 1.5 ± 0.07 μg/mL after 24, 48 and 72 hours treatment, respectively. ZER significantly (P < 0.05) arrested Jurkat cells at the G2/M phase of the cell cycle. The antiproliferative effect of ZER on Jurkat cells was through the apoptotic intrinsic pathway via the activation of caspase-3 and -9. The results showed that ZER can be further developed into a safe chemotherapeutic compound for the treatment of cancers, especially leukemia.

Ikeo K, Oshima T, Shan J, et al.
Junctional adhesion molecule-A promotes proliferation and inhibits apoptosis of gastric cancer.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):540-5 [PubMed] Related Publications
BACKGROUND/AIMS: Junctional adhesion molecules (JAMs) are known as integral constituents of cellular tight junctions. However, the functions of JAMs in cancer tissues are controversial and the function of JAM-A in gastric cancer is unclear. Acordingly, we investigated the function of JAM-A in gastric epithelial and gastric cancer cell proliferation, invasion and apoptosis.
METHODOLOGY: A normal rat gastric mucosa-derived cell line (RGM1), a rat gastric cancer-like cell line established from RGM1 (RGK1), and a human gastric cancer cell line (NCI-N87) were used in this study. To examine the expression of junctional proteins, immunoblotting and immunofluorescent staining were performed with specific antibodies (JAM-A, claudins, occludin and ZO-1). JAM-A was knocked down by small interfering RNA.
RESULTS: RGM1 and RGK1 expressed JAM-A, occludin and ZO-1 but not claudins. RGK1 were significantly more invasive than RGM1. JAM-A knock-down significantly decreased the proliferation and the invasion of RGK1 but not of RGM1. JAM-A knock-down significantly decreased the proliferation of NCI-N87 cells and significantly decreased expression of the anti-apoptotic protein Bcl-xL but not the expression of AKT or Mcl-1.
CONCLUSIONS: JAM-A promotes proliferation and inhibits apoptosis of gastric cancer, suggesting that it has a pivotal role in gastric cancer progression.

Abu-Dahab R, Abdallah MR, Kasabri V, et al.
Mechanistic studies of antiproliferative effects of Salvia triloba and Salvia dominica (Lamiaceae) on breast cancer cell lines (MCF7 and T47D).
Z Naturforsch C. 2014 Nov-Dec; 69(11-12):443-51 [PubMed] Related Publications
Ethanol extracts obtained from two Salvia species, S. triloba and S. dominica, collected from the flora of Jordan, were evaluated for their antiproliferative activity against MCF7 and T47D breast cancer cell lines by the sulforhodamine B assay. The ethanol extracts were biologically active with IC50 values of (29.89 ±0.92) and (38.91 ±2.44) μg/mL for S. triloba against MCF7 and T47D cells, respectively, and (5.83 ±0.51) and (12.83 ±0.64) μg/mL for S. dominica against MCF7 and T47D cells, respectively. Flow cytometry analysis and the annexinV-propidium iodide (PI) assay revealed apoptosismediated, and to a lesser extent necrosis-induced, cell death by the S. triloba and S. dominica ethanolic extracts in T47D cells. The mechanism of apoptosis was further investigated by determining the levels of p53, p21/WAF1, FasL (Fas ligand), and sFas (Fas/APO-1). The extract from S. triloba induced a more pronounced enrichment in cytoplasmic mono- and oligonucleosomes than that from S. dominica (p < 0:05) in T47D cells. In response to the extract from S. dominica, but not from S. triloba, the proapoptotic efficacy was specifically regulated by p21. Extracts from both Salvia spp. did not enhance p53 levels, and apoptosis induced by them was not caspase-8- or sFas/FasL-dependent. Thus, our findings indicate that S. triloba and S. dominica ethanolic extracts may be useful in breast cancer management/treatment via proapoptotic cytotoxic mechanisms.

Kouri FM, Hurley LA, Daniel WL, et al.
miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma.
Genes Dev. 2015; 29(7):732-45 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood-brain/blood-tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

Peng W, Wu JG, Jiang YB, et al.
Antitumor activity of 4-O-(2″-O-acetyl-6″-O-p-coumaroyl-β-D-glucopyranosyl)-p-coumaric acid against lung cancers via mitochondrial-mediated apoptosis.
Chem Biol Interact. 2015; 233:8-13 [PubMed] Related Publications
This study was aimed to investigate antitumor activity of 4-O-(2″-O-acetyl-6″-O-p-coumaroyl-β-D-glucopyranosyl)-p-coumaric acid (4-ACGC) against lung cancer and its mechanisms. The anti-proliferative effects of 4-ACGC on lung cancer cell lines including A549, NCI-H1299, HCC827 were evaluated by MTT method and the IC50 values were calculated, and subsequently a mice xenograft model of A549 was established to investigate the antitumor effect of 4-ACGC in vivo. Furthermore, the apoptosis of the A549 cells was determined by fluorescence microscope by staining with Hoechst 33324 and flow cytometer by staining with FITC conjugated Annexin V/PI, and the further mechanisms were investigated by Western blotting. Our results demonstrated that 4-ACGC possessed notable anti-tumor activity on lung cancer in vivo and in vitro; the mechanisms were involved in inducing mitochondria-mediated apoptosis via up-regulations of caspase-3, caspase-9, Bad and Bax, and down-regulation of Bcl-2. Collectively, our results indicated that the 4-ACGC could be treated as a new candidate for treatment of lung cancer in the future.

Joo EJ, Chun J, Ha YW, et al.
Novel roles of ginsenoside Rg3 in apoptosis through downregulation of epidermal growth factor receptor.
Chem Biol Interact. 2015; 233:25-34 [PubMed] Related Publications
Ginsenoside Rg3 (Rg3), a pharmacologically active compound from red ginseng, has been reported to induce cell death in various cancer cell lines, although the specific mechanisms have not been well established. In the present study, Rg3 treatment to A549 human lung adenocarcinoma led to cell death via not only apoptotic pathways but also the downregulation of epidermal growth factor receptor (EGFR). We used cross-linker and cell enzyme-linked immunosorbent assays to show that Rg3 inhibited EGFR dimerization by EGF stimulation and caused EGFR internalization from the cell membrane. Among several important phosphorylation sites in cytoplasmic EGFR, Rg3 increased the phosphorylation of tyrosine 1045 (pY1045) and serine 1046/1047 (pS1046/1047) for EGFR degradation and coincidently, attenuated pY1173 and pY1068 for mitogen-activated protein kinase activity. These effects were amplified under EGF-pretreated Rg3 stimulation. In vivo experiments showed that the average volume of the tumors treated with 30 mg/kg of Rg3 was significantly decreased by 40% compared with the control. Through immunohistochemistry, we detected the fragmentation of DNA, the accumulation of Rg3, and the reduction of EGFR expression in the Rg3-treated groups. Here, we provide the first description of the roles of Rg3 in the reduction of cell surface EGFR, the attenuation of EGFR signal transduction, and the eventual activation of apoptosis in A549 human lung adenocarcinoma.

Zhang Y, Hao Y, Sun Q, Peng C
Role of Smac in apoptosis of lung cancer cells A549 induced by Taxol.
Clin Lab. 2015; 61(1-2):17-21 [PubMed] Related Publications
BACKGROUND: A series of structurally unique second mitochondria-derived activators of caspase (Smac) that act as antagonists of inhibitor of apoptosis proteins (IAPs) directly have been discovered and have been shown to promote chemotherapy-induced apoptosis. In this study, we investigate the role of Smac in Taxol-induced apoptosis of lung cancer cell in vitro.
METHODS: PcDNA3.1/Smac recombinants were transfected into the non-small cell lung cancer cell line A549. Smac expression was detected by RT-PCR and Western blot. The invasive ability of cells was examined. Flow cytometry was used to analyze apoptosis of cells induced by Taxol with Annexin V/PI double staining technique.
RESULTS: Smac expression was significantly higher in the PcDNA3.1/Smac recombinant group than in the untransfected group at mRNA and protein level (p < 0.05) and lower invasion through a basal membrane was apparent after transfection (p < 0.05). A small number of cells were promoted to apoptosis in the PcDNA3.1/Smac group. There were significant differences compared to the empty vector group and control group. The apoptosis rate was significantly higher in PcDNA3.1/Smac + Taxol group than in other groups (p < 0.05).
CONCLUSIONS: Transfected Smac can enhance the chemosensitivity of the non-small cell lung cancer cell line A549 to Taxol.

Qiu JJ, Wang Y, Ding JX, et al.
The long non-coding RNA HOTAIR promotes the proliferation of serous ovarian cancer cells through the regulation of cell cycle arrest and apoptosis.
Exp Cell Res. 2015; 333(2):238-48 [PubMed] Related Publications
HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 and OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression.

Tang C, Zhao Y, Huang S, et al.
Influence of Artemisia annua extract derivatives on proliferation, apoptosis and metastasis of osteosarcoma cells.
Pak J Pharm Sci. 2015; 28(2 Suppl):773-9 [PubMed] Related Publications
Regarding the Artemisia annua extract derivatives called dihydroarteminin (DHA) as the object, we studied about its influence to the proliferation, apoptosis and metastasis of human osteosarcoma cells. First, we cultured in vitro the osteosarcoma cell strain and divided them into groups, then detected the cell proliferation, apoptosis and cell metastasis, etc by multiple measurement technique. Finally, we observed the influence of DHA to human osteosarcoma cells. Osteosarcoma cells were all sensitive to DHA, and the appropriate concentration range was 10~40μM. DHA could effectively restrain its protein expression, and there was a significant difference between experimental group and control group. These finding suggest that, the Artemisia annua extract derivatives (DHA) has a biological effect of observably restraining the proliferation and metastasis of human osteosarcoma cells and promoting the tumour cell apoptosis.

Liu ZM, Tseng HY, Cheng YL, et al.
TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis.
Toxicol Appl Pharmacol. 2015; 285(1):41-50 [PubMed] Related Publications
Arsenic trioxide (ATO) is a multi-target drug approved by the Food and Drug Administration as the first-line chemotherapeutic agent for the treatment of acute promyelocytic leukemia. In addition, several clinical trials are being conducted with arsenic-based drugs for the treatment of other hematological malignancies and solid tumors. However, ATO's modest clinical efficacy on some cancers, and potential toxic effects on humans have been reported. Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue. Previously, we demonstrated that the JNK-induced complex formation of phosphorylated c-Jun and TG-interacting factor (TGIF) antagonizes ERK-induced cyclin-dependent kinase inhibitor CDKN1A (p21(WAF1/CIP1)) expression and resultant apoptosis in response to ATO in A431 cells. Surprisingly, at low-concentrations (0.1-0.2 μM), ATO increased cellular proliferation, migration and invasion, involving TGIF expression, however, at high-concentrations (5-20 μM), ATO induced cell apoptosis. Using a promoter analysis, TGIF was transcriptionally regulated by ATO at the FOXO3A binding site (-1486 to -1479bp) via the c-Src/EGFR/AKT pathway. Stable overexpression of TGIF promoted advancing the cell cycle into the S phase, and attenuated 20 μM ATO-induced apoptosis. Furthermore, blockage of the AKT pathway enhanced ATO-induced CDKN1A expression and resultant apoptosis in cancer cells, but overexpression of AKT1 inhibited CDKN1A expression. Therefore, we suggest that TGIF is transcriptionally regulated by the c-Src/EGFR/AKT pathway, which plays a role as a negative regulator in antagonizing ATO-induced CDKN1A expression and resultant apoptosis. Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO.

Saleh AM, El-Abadelah MM, Aziz MA, et al.
Antiproliferative activity of the isoindigo 5'-Br in HL-60 cells is mediated by apoptosis, dysregulation of mitochondrial functions and arresting cell cycle at G0/G1 phase.
Cancer Lett. 2015; 361(2):251-61 [PubMed] Related Publications
Our new compound, 5'-Br [(E)-1-(5'-bromo-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f]quinoline-8-carboxylic acid], had shown strong, selective antiproliferative activity against different cancer cell lines. Here, we aim to comprehensively characterize the mechanisms associated with its cytotoxicity in the human promyelocytic leukemia HL-60 cells. We focused at studying the involvement of apoptotic pathway and cell cycle effects. 5'-Br significantly inhibited proliferation by inducing caspase-dependent apoptosis. Involvement of caspase independent mechanism is also possible due to observed inability of z-VAD-FMK to rescue apoptotic cells. 5'-Br was found to trigger intrinsic apoptotic pathway as indicated by depolarization of the mitochondrial inner membrane, decreased level of cellular ATP, modulated expression and phosphorylation of Bcl-2 leading to loss of its association with Bax, and increased release of cytochrome c. 5'-Br treated cells were found arrested at G0/G1 phase with modulation in protein levels of cyclins, dependent kinases and their inhibitors. Expression and enzymatic activity of CDK2 and CDK4 was found inhibited. Retinoblastoma protein (Rb) phosphorylation was also inhibited whereas p21 protein levels were increased. These results suggest that the antiproliferative mechanisms of action of 5'-Br could involve apoptotic pathways, dysregulation of mitochondrial functions and disruption of cell cycle checkpoint.

Li T, Su L, Lei Y, et al.
DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells.
J Biol Chem. 2015; 290(17):11108-18 [PubMed] Article available free on PMC after 24/04/2016 Related Publications
TNFRSF10A and TNFRSF10B are cell surface receptors that bind to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mediate the extrinsic pathway of apoptosis. However, the mechanisms of transcriptional regulation of TNFRSF10A and TNFRSF10B remain largely uncharacterized. In this study, two putative DDIT3 binding sites (-1636/-1625; -374/-364) and a putative AP-1 binding site (-304/-298) were identified in the TNFRSF10A promoter region. We found that DDIT3 interacts with phospho-JUN, and the DDIT3·phospho-JUN complex binds to the AP-1 binding site (-304/-298) within the TNFRSF10A promoter region. In addition, we confirmed that KAT2A physically interacts with the N-terminal region (amino acids 1-26) of DDIT3. Importantly, knockdown of KAT2A down-regulated TNFRSF10A and TNFRSF10B and dramatically decreased promoter activity of cells transfected with luciferase reporter plasmid containing the AP-1 binding site (-304/-298) of the TNFRSF10A promoter, as well as cells transfected with luciferase reporter plasmid containing DDIT3 binding site (-276/-264) of the TNFRSF10B promoter. ChIP results suggest that KAT2A may participate in a KAT2A·DDIT3·phospho-JUN complex, or may participate in a KAT2A·DDIT3 complex and acetylate H3K9/K14, respectively. Moreover, we verified that TNFRSF10A mediates apoptosis triggered by endoplasmic reticulum stress in human lung cancer cells. Collectively, we demonstrate that DDIT3 and KAT2A cooperatively up-regulate TNFRSF10A and TNFRSF10B. Our findings highlight novel mechanisms underlying endoplasmic reticulum stress-induced TNFRSF10A and TNFRSF10B expressions and apoptosis. These findings will be helpful for elucidating mechanisms related to anticancer drugs in mediating apoptosis.

So KS, Rho JK, Choi YJ, et al.
AKT/mTOR down-regulation by CX-4945, a CK2 inhibitor, promotes apoptosis in chemorefractory non-small cell lung cancer cells.
Anticancer Res. 2015; 35(3):1537-42 [PubMed] Related Publications
AIM: The response to chemotherapeutic drugs in non-small cell lung cancer (NSCLC) is unsatisfactory, leading to poor outcomes. This study the aimed to investigates anticancer effects of CX-4945, a potent casein kinase II (CK2) inhibitor, in chemorefractory NSCLC cells.
MATERIALS AND METHODS: Cell proliferation and apoptosis assay were carried-out by annexin V-FITC and FACScan after drug treatment with paclitaxel, cisplatin and CX-4945. AKT/mTOR and CK2α signals were measured by western blotting. Treatment was carried-out using siRNA to inhibit CK2α.
RESULTS: Paclitaxel, and cisplatin effectively inhibited cell proliferation and induced apoptosis in A549 cells, while not in H1299, Calu-1 and H358 cells. In these chemorefractory cell lines, AKT signalling was maintained despite drug treatment. However, CX-4945 suppressed cell growth, with cell-cycle arrest at G2/M phase and induced apoptosis with an increase of cleaved caspase-3 and PARP1 in a dose-dependent manner. Accordingly, AKT and its downstream signals such as mTOR and p70S6K were down-regulated by CX-4945. Transfection of CK2α siRNA had similar effects to CX-4945 treatment on cell proliferation and apoptosis.
CONCLUSION: CX-4945 shows a promising anticancer action through down-regulation of AKT/mTOR signals, suggesting its possible application for treatment of chemorefractory lung cancer.

Kostopoulos A, Papageorgiou E, Koutsilieris M, Sivolapenko G
PCK3145 inhibits proliferation and induces apoptosis in breast and colon cancer cells.
Anticancer Res. 2015; 35(3):1377-84 [PubMed] Related Publications
AIM: To explore the effects of PCK3145 beyond prostate cancer.
MATERIALS AND METHODS: Using Trypan blue, MTT proliferation assays, cell cycle and apoptosis analysis, we assessed the effects of PCK3145 on prostate (PC-3), breast (MCF-7) and colon (HT-29) human cancer cell lines and in osteosarcoma (MG-63) cells; any synergistic effects with docetaxel and oxaliplatin were also explored.
RESULTS: PCK3145 inhibited proliferation and induced apoptosis of PC-3, MCF-7 and HT-29 cells in a dose- and time-dependent manner but not in the MG-63 cell line, consistent with the low expression of the laminin receptor (LR) in the latter cell line. PCK3145 produced rapid (within 5 min) and transient (up to 60 min) activation of MEK and ERK1/2. Synergistic effects were observed with docetaxel and oxaliplatin.
CONCLUSION: PCK3145 can exert anticancer activity not only on prostate but also on breast and colon cancer cells, possibly through LR-mediated activation of MEK and ERK1/2 phosphorylation.

Ngobili TA, Shah H, Park JP, et al.
Remodeling of tannic acid crosslinked collagen type I induces apoptosis in ER+ breast cancer cells.
Anticancer Res. 2015; 35(3):1285-90 [PubMed] Related Publications
BACKGROUND: The naturally-occurring phytochemical tannic acid (TA) has anticancer properties. We have demonstrated that estrogen receptor-positive (ER+) breast cancer cells are more sensitive to effects of TA than triple-negative breast cancer cells and normal breast epithelial cells. In the present study, cells were grown on TA-crosslinked collagen beads. Growing cells remodel collagen and release TA, which affects attached cells.
MATERIALS AND METHODS: The ER+ breast cancer cell line MCF7 and the normal breast epithelial cell line MCF10A were grown on TA-crosslinked collagen beads in roller bottles. Concentrations of TA in conditioned media were determined. Induced apoptosis was imaged and quantified. Caspase gene expression was calculated by real-time polymerase chain reaction (PCR).
RESULTS: Both cell lines attached and grew on TA-crosslinked collagen beads where they remodeled collagen and released TA into surrounding medium. Released TA induced caspase-mediated apoptosis.
CONCLUSION: TA induced apoptosis in a concentration-dependent manner, with ER+ MCF7 cells displaying more sensitivity to effects of TA.

Chakraborty AK, Mehra R, Digiovanna MP
Co-targeting ER and HER family receptors induces apoptosis in HER2-normal or overexpressing breast cancer models.
Anticancer Res. 2015; 35(3):1243-50 [PubMed] Related Publications
BACKGROUND: Estrogen receptor (ER) and human epidermal growth factor receptor (HER) family receptors interact in breast cancer; co-targeting these receptors is of interest. We previously reported on a synergistic growth inhibition for the combination of trastuzumab plus tamoxifen in HER2+/ER+ BT474 cells, but no induction of apoptosis. Herein we describe the effects of co-targeting in models of differing HER2 overexpression status (MCF7 HER2-normal/ER+, BT474 HER2-overexpressing/ER+).
MATERIALS AND METHODS: Assays of proliferation were carried-out using WST-1, cell cycle using flow cytometry, and apoptosis by determination of sub-G1 population and by annexin-V.
RESULTS: Combining a dual HER2/EGFR kinase inhibitor with anti-estrogens induces apoptosis of BT474 cells. Furthermore, in MCF7 cells, despite HER2-normal status and lack of response to single-agent HER2 inhibitors, addition of HER2 inhibitors or dual HER2/EGFR inhibitor to anti-estrogens augments the antiproliferative effect of anti-estrogens, and converts the drug effect from cytostatic to apoptosis-inducing.
CONCLUSION: ER-HER co-targeting enhanced the antitumor effects and can bring about effects of targeting HER2 in models of HER2-normal breast cancer.

Lin TY, Lee CC, Chen KC, et al.
Inhibition of RNA transportation induces glioma cell apoptosis via downregulation of RanGAP1 expression.
Chem Biol Interact. 2015; 232:49-57 [PubMed] Related Publications
The prognosis of glioblastoma remains poor, even treatment with surgery, radiation, or chemotherapy. Therefore, it is still important to develop a new strategy for treatment of glioblastoma. Previous reports demonstrated that rRNA is produced at abnormally high levels in tumor cells. Nuclear export of all non-coding RNAs are known to depend on RanGTPase system. Hydrolyzation of RanGTP-RNA complex by RanGTPase activating protein 1 (RanGAP1) releases RNA from nucleus to cytoplasm. Therefore, inhibition of RNA transportation would be a useful strategy to affect cancer cell fate. In this study, 5-30 μM of oridonin, a natural diterpenoid compound isolated from the traditional Chinese medicine, Rabdosia rubescens, induced U87MG glioma cell apoptosis and RNA accumulation in nucleus at 12h-time point. Before U87MG cell apoptosis, the RanGAP1 protein amount decreased and RanGTP accumulated in nucleus as respectively determined by immunoprecipitation and immunofluorescence, suggesting that decrease of RanGAP1 may result in nuclear entrapment of RanGTP and RNA, and then induce U87MG cell death. In contrast, over-expression of the RanGAP1 protein reversed oridonin-induced U87MG cell apoptosis. Hence, we demonstrated that downregulation of the RanGAP1 protein level by oridonin may result in RNA accumulation in nucleus via nuclear entrapment of RanGTP which eventually led to the apoptosis of glioma cells.

Chodurek E, Kulczycka A, Orchel A, et al.
Effect of valproic acid on the proliferation and apoptosis of the human melanoma G-361 cell line.
Acta Pol Pharm. 2014 Nov-Dec; 71(6):917-21 [PubMed] Related Publications
Melanoma malignant is characterized by a high malignancy and low susceptibility to treatment. Due to these properties, there is a growing interest in compounds that would have the ability to inhibit proliferation, induce differentiation of tumor cells and initiate the apoptotic pathway. In vitro and in vivo research indicate that valproic acid (a histone deacetylase inhibitor) may have anti-cancer properties. In our study, the role of VPA on proliferation and apoptosis in G-361 human melanoma cell line was examined. Obtained results indicated that administration of VPA at concentrations above ≥ 1 mM led to significant inhibition of cell growth. Simultaneously, it was observed that VPA at higher concentrations (5 and 10 mM) caused an increase in caspase-3 activity.

Lopez J, Tait SW
Mitochondrial apoptosis: killing cancer using the enemy within.
Br J Cancer. 2015; 112(6):957-62 [PubMed] Article available free on PMC after 24/04/2016 Related Publications
Apoptotic cell death inhibits oncogenesis at multiple stages, ranging from transformation to metastasis. Consequently, in order for cancer to develop and progress, apoptosis must be inhibited. Cell death also plays major roles in cancer treatment, serving as the main effector function of many anti-cancer therapies. In this review, we discuss the role of apoptosis in the development and treatment of cancer. Specifically, we focus upon the mitochondrial pathway of apoptosis-the most commonly deregulated form of cell death in cancer. In this process, mitochondrial outer membrane permeabilisation or MOMP represents the defining event that irrevocably commits a cell to die. We provide an overview of how this pathway is regulated by BCL-2 family proteins and describe ways in which cancer cells can block it. Finally, we discuss exciting new approaches aimed at specifically inducing mitochondrial apoptosis in cancer cells, outlining their potential pitfalls, while highlighting their considerable therapeutic promise.

Dong Y, Liang C, Zhang B, et al.
Bortezomib enhances the therapeutic efficacy of dasatinib by promoting c-KIT internalization-induced apoptosis in gastrointestinal stromal tumor cells.
Cancer Lett. 2015; 361(1):137-46 [PubMed] Related Publications
Dasatinib-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of dasatinib target proteins, such as c-KIT and PDGFRβ, attenuates the therapeutic efficiency of dasatinib. Combination therapy which inhibits the activation of dasatinib target proteins may enhance the cytotoxicity of dasatinib in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of dasatinib-treated GIST-T1 cells, whereas GIST-T1 cells showed little dasatinib cytotoxicity when treated with dasatinib alone, as the upregulation of c-KIT caused by dasatinib itself interfered with the inhibition of c-KIT and PDGFRβ phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf-1, which was originally bound to the c-KIT-Hsp90β-Apaf-1 complex, induced primary apoptosis in GIST-T1 cells. Combined treatment with bortezomib plus dasatinib caused cell cycle arrest in the G1 phase through inactivation of PDGFRβ and promoted bortezomib-induced apoptosis in GIST-T1 cells. Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs.

Wu S, Guo Y, Wu Y, et al.
Omega-3 free fatty acids inhibit tamoxifen-induced cell apoptosis.
Biochem Biophys Res Commun. 2015; 459(2):294-9 [PubMed] Related Publications
Fish oil, which contains omega-3 fatty acids mainly in the form of triglycerides, has benefits for reducing breast cancer risk, similar to tamoxifen action. However, it remains to be elucidated whether the combination of omega-3 free fatty acid (ω-3FFA) with tamoxifen leads to improved treatment in breast cancer. In this study, we observed that ω-3FFA induces MCF-7 cell apoptosis to suppress cell growth. The treatment of breast cancer cells with ω-3FFA attenuated tamoxifen-induced cell apoptosis. ω-3FFA and tamoxifen significantly increased Erk1/2 and Akt phosphorylation levels in a dose and time dependent manner. Compared to ω-3FFA alone, the combination of tamoxifen with ω-3FFA significantly increased Erk1/2 and Akt phosphorylation levels. Because Erk1/2 and Akt activation has been linked to tamoxifen-related anti-estrogen resistance in breast cancer patients, these results indicate that ω-3FFA may interfere with the effects of tamoxifen in the prevention of breast cancer risk.

Tcherniuk SO, Oleinikov AV
Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295.
Cancer Lett. 2015; 361(1):97-103 [PubMed] Related Publications
Human kinesin CENP-E is an attractive target for cancer chemotherapy. The allosteric CENP-E inhibitor GSK923295 was proposed as a promising anticancer compound with potent cytostatic effect. In our work, we have analyzed the influence of the Pgp efflux pump on the cytostatic effect of GSK923295. We have demonstrated that multidrug resistant MESSA Dx5 cells overexpressing Pgp are 70-80 times more resistant to GSK923295 than their parental counterpart MESSA cells. Addition of 20 µM verapamil restored the drug sensibility of MESSA Dx5 cells. Combinations of GSK923295 with verapamil showed nearly additive effects in MESSA and synergistic effects in MESSA Dx5 cells. Our results demonstrate that tumors possessing Pgp could be more resistant to GSK923295, and that overexpression of Pgp can decrease the therapeutic effect of this drug. Development of structural analogs of GSK923295 which would not be a substrate of the Pgp efflux pump or addition of Pgp pump inhibitors can significantly improve the cytostatic effect of this drug.

Zuo C, Qiu X, Liu N, et al.
Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma.
Exp Cell Res. 2015; 333(2):316-26 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4׳,6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors.

Odum N
Malignant TOXication of T cells.
Blood. 2015; 125(9):1361-2 [PubMed] Related Publications
In this issue of Blood, Huang et al show that aberrant expression of TOX plays a central role in malignant survival, proliferation, and tumor formation in cutaneous T-cell lymphoma (CTCL).

Mishima Y, Santo L, Eda H, et al.
Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death.
Br J Haematol. 2015; 169(3):423-34 [PubMed] Related Publications
Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.

Yi J, Wu L, Liu Z, et al.
High-intensity focused ultrasound ablation induced apoptosis in human hepatocellular carcinoma.
Hepatogastroenterology. 2014 Nov-Dec; 61(136):2336-9 [PubMed] Related Publications
BACKGROUND/AIMS: To evaluate the effect of high-intensity ultrasound (HIFU) ablation on human hepatocellular carcinoma tissues and apoptotic proteins (bcl-2 and p-53).
METHODOLOGY: Patients with hepatocellular carcinoma at stage B were treated with HIFU ablation. Levels of bcl-2 and p53 protein and the apoptosis rate were evaluated both in the pre-treatment and post-treatment tissue specimens using immunochemistry and TUNEL methods, respectively.
RESULTS: After HIFU ablation, p53 protein levels were significantly increased around the coagulation necrosis area, whereas, the level of bcl-2 was significantly decreased. More apoptosis cells were found post ablation compared with those in the pretreatment tissues. Additionally, no significant correlation was found between p53/bcl-2 levels and apoptotic index.
CONCLUSIONS: HIFU ablation may exert promote the apoptosis of hepatocellular carcinoma cells and the effect has a closely association with the change of p53 and bcl-2 expression.

Stuhldreier F, Kassel S, Schumacher L, et al.
Pleiotropic effects of spongean alkaloids on mechanisms of cell death, cell cycle progression and DNA damage response (DDR) of acute myeloid leukemia (AML) cells.
Cancer Lett. 2015; 361(1):39-48 [PubMed] Related Publications
We investigated cytotoxic mechanisms evoked by the spongean alkaloids aaptamine (Aa) and aeroplysinin-1 (Ap), applied alone and in combination with daunorubicin, employing acute myeloid leukemia (AML) cells. Aa and Ap reduced the viability of AML cells in a dose dependent manner with IC50 of 10-20 µM. Ap triggered apoptotic cell death more efficiently than Aa. Both alkaloids increased the protein level of S139-phosphorylated H2AX (γH2AX), which however was independent of the induction of DNA damage. Expression of the senescence markers p21 and p16 was increased, while the phosphorylation level of p-Chk-2 was reduced following Aa treatment. As a function of dose, Aa and Ap protected or sensitized AML cells against daunorubicin. Protection by Aa was paralleled by reduced formation of ROS and lower level of DNA damage. Both Aa and Ap attenuated daunorubicin-stimulated activation of the DNA damage response (DDR) as reflected on the levels of γH2AX, p-Kap-1 and p-Chk-1. Specifically Ap restored the decrease in S10 phosphorylation of histone H3 resulting from daunorubicin treatment. The cytoprotective effects of Aa and Ap were independent of daunorubicin import/export. Both Aa and Ap abrogated daunorubicin-induced accumulation of cells in S-phase. Inhibition of DNA synthesis was specific for Ap. The data show that Aa and Ap have both congruent and agent-specific pleiotropic effects that are preferential for anticancer drugs. Since Ap showed a broader spectrum of anticancer activities, this compound is suggested as novel lead compound for forthcoming in vivo studies elucidating the usefulness of spongean alkaloids in AML therapy.

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