"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)
Cancer Research UK Includes Cell death (apoptosis) news from Cancer Research UK
Introduction to Cancer Biology (Part 2): Loss of Apoptosis
mechanismsinmedicine.com Educational animation. "Apoptosis or "programmed cell death" is a mechanism by which organisms limit the growth and replication of cells. Loss of apoptosis is one of the key mechanisms behind cancer..."
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.
Chang LC, Yu YL, Liu CY, et al. The newly synthesized 2-arylnaphthyridin-4-one, CSC-3436, induces apoptosis of non-small cell lung cancer cells by inhibiting tubulin dynamics and activating CDK1. Cancer Chemother Pharmacol. 2015; 75(6):1303-15 [PubMed] Related Publications
PURPOSE: To investigate the anticancer therapeutic potential of a new synthetic compound, 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), on non-small cell lung cancer (NSCLC) cells. METHODS: Cell viability was determined by MTT assay. Cell cycle distribution was assessed by propidium iodide staining and subjected to flow cytometry analysis. Protein expression was detected by western blot analysis. Pharmacological inhibitors and shRNAs were applied to examine the possible pathways involved CSC-3436-inhibited viability of NSCLC cells. RESULTS: CSC-3436 decreased NSCLC cell viability by inducing apoptosis. In vivo and in vitro tubulin polymerization assays revealed that CSC-3463 caused tubulin depolymerization by directly binding to the colchicine-binding site. Furthermore, CSC-3436 caused the mitotic arrest with a marked activation of cyclin-dependent kinase 1 (CDK1) and increased the expression of phospho-Ser/Thr-Pro mitotic protein monoclonal 2. The CDK1 inhibitor, roscovitine, reversed the CSC-3436-induced upregulation of CDK1 activity as well as the mitotic arrest. DNA damage response kinases, including ataxia telangiectasia mutated (ATM), ATM and Rad3-related, DNA-dependent protein kinase, checkpoint kinase 1, and checkpoint kinase 2, were phosphorylated and activated by CSC-3436. c-Jun N-terminal kinase was activated by CSC-3436 and involved in the regulation of mitotic arrest and apoptosis. CSC-3436-induced apoptosis was accompanied by the activation of pro-apoptotic factors FADD, TRADD, and RIP and the inactivation of anti-apoptotic proteins Bcl-2 and Bcl-xL, resulting in the cleavage and subsequent activation of caspases. CONCLUSIONS: Our results reveal the cellular events in which CSC-3436 induces tumor cell death and demonstrate that CSC-3436 is a potential tubulin-disrupting agent for antitumor therapy against NSCLC.
Zhang L, Wang H, Ding K, Xu J FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells. Toxicol Lett. 2015; 236(1):43-59 [PubMed] Related Publications
FTY720 is a potent immunosuppressant which has preclinical antitumor efficacy in various cancer models. However, its role in glioblastoma remains unclear. In the present study, we found that FTY720 induced extrinsic apoptosis, necroptosis and autophagy in human glioblastoma cells. Inhibition of autophagy by either RNA interference or chemical inhibitors attenuated FTY720-induced apoptosis and necrosis. Furthermore, autophagy, apoptosis and necrosis induction were dependent on reactive oxygen species-c-Jun N-terminal kinase-protein 53 (ROS-JNK-p53) loop mediated phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) pathway. In addition, receptor-interacting protein 1 and 3 (RIP1 and RIP3) served as an upstream of ROS-JNK-p53 loop. However, the phosphorylation form of FTY720 induced autophagy but not apoptosis and necroptosis. Finally, the in vitro results were validated in vivo in xenograft mouse of glioblastoma cells. In conclusion, the current study provided novel insights into understanding the mechanisms and functions of FTY720-induced apoptosis, necroptosis and autophagy in human glioblastoma cells.
Lu K, Liu C, Tao T, et al. MicroRNA-19a regulates proliferation and apoptosis of castration-resistant prostate cancer cells by targeting BTG1. FEBS Lett. 2015; 589(13):1485-90 [PubMed] Related Publications
MicroRNAs (miRNAs) play a significant role in tumor development. Recent studies indicate that miRNAs are implicated in prostate cancer (PCa). In this study, we found that miR-19a expression was significantly increased in castration-resistant prostate cancer (CRPC) tissues compared with androgen-dependent prostate cancer (ADPC) tissues. We found that inhibiting the overexpression of miR-19a in CRPC cells suppressed proliferation and increased apoptosis. Additionally, we found that miR-19a repressed BTG1 expression by binding to its 3'-untranslated region. The overexpression of BTG1 in CRPC cells significantly suppressed proliferation and increased apoptosis. We conclude that miR-19a regulates proliferation and apoptosis of CRPC cells by directly targeting the tumor suppressor gene BTG1.
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.
Karaca B, Degirmenci M, Ozveren A, et al. Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines. Cancer Chemother Pharmacol. 2015; 75(6):1273-80 [PubMed] Related Publications
PURPOSE: Docetaxel (DTX) is widely used for the treatment of metastatic prostate and breast cancers. Despite the clinical success of DTX, drug-related cumulative toxicity restricts its clinical use in cancer therapy. Thus, there is an urgent need for new therapeutic options. Octreotide (OCT) is a synthetic somatostatin analog that induces apoptosis in different cancer cell lines in vitro. In this study, we investigated the possible synergistic apoptotic effects of DTX in combination with OCT in prostate and breast cancer cell lines. METHODS: The XTT cell viability assay was used to determine cytotoxicity. Apoptosis was evaluated by Cell Death Detection ELISA(Plus) Kit. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. Levels of SSTR2 and SSTR5 proteins were determined by western blot analysis. RESULTS: DTX and OCT combination induced apoptosis in both breast and prostate cancer cells in a concentration- and time-dependent manner. Moreover, combination treatment resulted in inhibition of anti-apoptotic proteins such as Bcl-2 and Bcl-xL and induction of pro-apoptotic proteins Bax, Cytochrome c and IAPs in all of the tested cancer cell lines. SSTR2 and SSTR5 protein levels were induced as compared to any agent alone. CONCLUSIONS: These results indicate that this combination treatment is a significant inducer of apoptosis in a synergistic manner in breast and prostate cancer cells. This strong synergism helps to lower the dose of DTX in both types of cancers, thus letting DTX to be used for longer periods by delaying resistance development and lesser side effects.
Pimolsanti R, Wongkajornsilpa A, Chotiyarnwong P, et al. Effects of thermoablation with or without caffeine on giant cell tumour of bone. J Orthop Surg (Hong Kong). 2015; 23(1):95-9 [PubMed] Related Publications
PURPOSE: To evaluate the effect of caffeine on the apoptosis rate of giant cell tumour of bone cells during thermoablation. METHODS: Giant cell tumour of bone tissue (2 cm3) was collected from 10 patients. Cells were incubated at 37ºC, 40ºC, 45ºC, 50ºC, 52.5ºC, and 55ºC for 20 minutes (3 tubes for each temperature). Caffeine was added to the tubes in amounts of 0 μg/ml (control), 50 μg/ml, and 100 μg/ml. The apoptotic effect of thermoablation with or without caffeine was evaluated. RESULTS: In all test conditions, the apoptotic rate of tumour cells increased when the temperature increased. Compared with controls (no caffeine), adding 50 or 100 μg/ml of caffeine did not increase the apoptotic rate significantly at 40ºC to 52.5ºC. Caffeine had no enhancing effect at any temperature. Conversely, at 55ºC, the apoptotic rate was lower when 100 μg/ml of caffeine was added than when no or 50 μg/ml of caffeine added (p=0.045). CONCLUSION: Thermoablation at 40ºC to 52.5ºC for 20 minutes increased the apoptosis rate of giant cell tumour of bone cells. Caffeine had no enhancing effect at any temperature. Conversely, at 55ºC, caffeine had cytoprotective effects on the tumour cells against thermoablation.
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.
Wan Y, Zheng X, Chen H, et al. Splicing function of mitotic regulators links R-loop-mediated DNA damage to tumor cell killing. J Cell Biol. 2015; 209(2):235-46 [PubMed] Article available free on PMC after 27/10/2015 Related Publications
Although studies suggest that perturbing mitotic progression leads to DNA damage and p53 activation, which in turn lead to either cell apoptosis or senescence, it remains unclear how mitotic defects trigger p53 activation. We show that BuGZ and Bub3, which are two mitotic regulators localized in the interphase nucleus, interact with the splicing machinery and are required for pre-mRNA splicing. Similar to inhibition of RNA splicing by pladienolide B, depletion of either BuGZ or Bub3 led to increased formation of RNA-DNA hybrids (R-loops), which led to DNA damage and p53 activation in both human tumor cells and primary cells. Thus, R-loop-mediated DNA damage and p53 activation offer a mechanistic explanation for apoptosis of cancer cells and senescence of primary cells upon disruption of the dual-function mitotic regulators. This demonstrates the importance of understanding the full range of functions of mitotic regulators to develop antitumor drugs.
Haque A, Rahman MA, Fuchs JR, et al. FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway. Cancer Lett. 2015; 363(2):166-75 [PubMed] Article available free on PMC after 28/07/2016 Related Publications
Unlike chemotherapy drugs, the safety of natural compounds such as curcumin has been well established. However, the potential use of curcumin in cancer has been compromised by its low bioavailability, limited tissue distribution and rapid biotransformation leading to low in vivo efficacy. To circumvent these problems, more potent and bioavailable analogs have been synthesized. In the current study, we investigated the mechanism of anti-tumor effect of one such analog, FLLL12, in lung cancers. IC50 values measured by sulforhodamine B (SRB) assay at 72 h and apoptosis assays (annexin V staining, cleavage of PARP and caspase-3) suggest that FLLL12 is 5-10-fold more potent than curcumin against a panel of premalignant and malignant lung cancer cell lines, depending on the cell line. Moreover, FLLL12 induced the expression of death receptor-5 (DR5). Ablation of the expression of the components of the extrinsic apoptotic pathway (DR5, caspase-8 and Bid) by siRNA significantly protected cells from FLLL12-induced apoptosis (p < 0.05). Analysis of mRNA expression revealed that FLLL-12 had no significant effect on the expression of DR5 mRNA expression. Interestingly, inhibition of global phosphatase activity as well as protein tyrosine phosphatases (PTPs), but not of alkaline phosphatases, strongly inhibited DR5 expression and significantly inhibited apoptosis (p < 0.05), suggesting the involvement of PTPs in the regulation of DR5 expression and apoptosis. We further showed that the apoptosis is independent of p53 and p73. Taken together, our results strongly suggest that FLLL12 induces apoptosis of lung cancer cell lines by posttranscriptional regulation of DR5 through activation of protein tyrosine phosphatase(s).
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.
De Miguel D, Gallego-Lleyda A, Anel A, Martinez-Lostao L Liposome-bound TRAIL induces superior DR5 clustering and enhanced DISC recruitment in histiocytic lymphoma U937 cells. Leuk Res. 2015; 39(6):657-66 [PubMed] Related Publications
Human Apo2-Ligand/TRAIL is a promising antitumor agent. Our group demonstrated that TRAIL was physiologically released to the extracellular medium inserted in lipid vesicles, known as exosomes. Recently we demonstrated that artificial lipid nanoparticles coated with bioactive TRAIL (LUV-TRAIL), which resemble the natural exosomes, greatly improved TRAIL activity compared with the soluble form of this death ligand and were able to induce apoptosis in hematological malignancies. In this study we have deepened the underlying mechanism of action of LUV-TRAIL in hematologic cells. Using histiocytic lymphoma U937 cells, we demonstrated that TRAIL signaling almost exclusively depends on DR5 despite these cells expressing high amounts of DR4, and proved that LUV-TRAIL's higher pro-apoptotic effect relies on its superior ability to induce DR5 clustering on cell surface, therefore enhancing DISC recruitment and triggering caspase activation more efficiently than the soluble form of TRAIL.
Papaevangelou E, Almeida GS, Jamin Y, et al. Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy. Br J Cancer. 2015; 112(9):1471-9 [PubMed] Article available free on PMC after 28/04/2016 Related Publications
BACKGROUND: Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) magnetic resonance imaging (MRI) for imaging cell death induced by either a cytotoxic drug (irinotecan), or the apoptosis-inducing agent birinapant, in human tumour xenografts in vivo. METHODS: Nude mice bearing human SW620 colon carcinoma xenografts were treated with vehicle, irinotecan (50 mg kg(-1)) or birinapant (30 mg kg(-1)) for up to 5 days. DW-MRI was performed prior to and on days 1, 3 and 5 during treatment. Assessment of tumour apoptosis and necrosis ex vivo was used to validate the imaging findings. RESULTS: Both irinotecan and birinapant induced significant tumour growth delay. Irinotecan induced a small increase in the tumour apparent diffusion coefficient (ADC) after 1 day, with a 20 and 30% increase at days 3 and 5 respectively. ADC was unchanged in the vehicle- and birinapant-treated tumours despite a growth delay in the latter. Histological analysis showed that irinotecan increased necrosis at days 3 and 5, and induced apoptosis after 1 day, compared with vehicle. Birinapant induced apoptosis after day 3, but had no effect on tumour necrosis. CONCLUSIONS: Tumour ADC changes after irinotecan treatment were associated with the induction of a mixture of necrotic and apoptotic cell death, whereas induction of apoptosis alone with birinapant was not sufficient to induce changes in tissue microstructure that were detectable with DW-MRI. ADC is a useful non-invasive biomarker for early detection of response to cytotoxic drugs, but false negatives may arise while detecting apoptotic response to birinapant.
Sorokin AV, Nair BC, Wei Y, et al. Aberrant Expression of proPTPRN2 in Cancer Cells Confers Resistance to Apoptosis. Cancer Res. 2015; 75(9):1846-58 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The protein tyrosine phosphatase receptor PTPRN2 is expressed predominantly in endocrine and neuronal cells, where it functions in exocytosis. We found that its immature isoform proPTPRN2 is overexpressed in various cancers, including breast cancer. High proPTPRN2 expression was associated strongly with lymph node-positive breast cancer and poor clinical outcome. Loss of proPTPRN2 in breast cancer cells promoted apoptosis and blocked tumor formation in mice, whereas enforced expression of proPTPRN2 in nontransformed human mammary epithelial cells exerted a converse effect. Mechanistic investigations suggested that ProPTPRN2 elicited these effects through direct interaction with TRAF2, a hub scaffold protein for multiple kinase cascades, including ones that activate NF-κB. Overall, our results suggest PTPRN2 as a novel candidate biomarker and therapeutic target in breast cancer.
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.
Ghosh S, Kumar A, Chandna S Connexin-43 downregulation in G2/M phase enriched tumour cells causes extensive low-dose hyper-radiosensitivity (HRS) associated with mitochondrial apoptotic events. Cancer Lett. 2015; 363(1):46-59 [PubMed] Related Publications
Enrichment of tumour cells in G2/M phases in vitro is known to be associated with low-dose hyper-radiosensitivity (HRS). These cell cycle phases also involve reduced expression of adhesion protein connexin-43 (Cx43). Therefore, we investigated the role of Cx43 in HRS. Asynchronous or G2/M enriched tumour cells (U87, BMG-1, HeLa) and normal primary fibroblasts (HDFn) were γ-irradiated at varying doses, with an asynchronous group separately subjected to Cx43-knockdown prior to irradiation. Cx43 level, gap junctional activity, clonogenic cell survival, cell growth/viability, mitochondrial alterations and other apoptosis-regulating events were studied. G2/M enrichment reduced Cx43 level by ~50% and caused considerable HRS at doses 10 cGy-30 cGy in all tumour cell lines. Cx43-knockdown to the same level (~60%) also elicited prominent HRS response in these cells. Quite important, radiosensitivity of primary HDFn cells remained unaltered by all these treatments. In Cx43-knockdown tumour cells, low-dose irradiation caused significant growth inhibition and apoptosis involving loss of MMP, cytochrome-c release and caspase-3 activation, thereby demonstrating the important cytoprotective role of Cx43. Therefore, this study significantly shows that Cx43 downregulation (a constitutive feature of G2/M phase) selectively renders tumour cells hypersensitive to low-dose radiation, and presents connexins as potential therapeutic targets.
Hirst AM, Simms MS, Mann VM, et al. Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells. Br J Cancer. 2015; 112(9):1536-45 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: In recent years, the rapidly advancing field of low-temperature atmospheric pressure plasmas has shown considerable promise for future translational biomedical applications, including cancer therapy, through the generation of reactive oxygen and nitrogen species. METHOD: The cytopathic effect of low-temperature plasma was first verified in two commonly used prostate cell lines: BPH-1 and PC-3 cells. The study was then extended to analyse the effects in paired normal and tumour (Gleason grade 7) prostate epithelial cells cultured directly from patient tissue. Hydrogen peroxide (H2O2) and staurosporine were used as controls throughout. RESULTS: Low-temperature plasma (LTP) exposure resulted in high levels of DNA damage, a reduction in cell viability, and colony-forming ability. H2O2 formed in the culture medium was a likely facilitator of these effects. Necrosis and autophagy were recorded in primary cells, whereas cell lines exhibited apoptosis and necrosis. CONCLUSIONS: This study demonstrates that LTP treatment causes cytotoxic insult in primary prostate cells, leading to rapid necrotic cell death. It also highlights the need to study primary cultures in order to gain more realistic insight into patient response.
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.
Lin X, Fang Q, Chen S, et al. Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway. Leuk Res. 2015; 39(5):544-52 [PubMed] Related Publications
There are few studies on the correlation between heme oxygenase-1 (HO-1) and acute myeloid leukemia (AML). We found that HO-1 was aberrantly overexpressed in the majority of AML patients, especially in patients with acute monocytic leukemia (M5) and leukocytosis, and inhibited the apoptosis of HL-60 and U937 cells. Moreover, silencing HO-1 prolonged the survival of xenograft mouse models. Further studies demonstrated that HO-1 suppressed the apoptosis of AML cells through activating the JNK/c-JUN signaling pathway. These data indicate a molecular role of HO-1 in inhibiting cell apoptosis, allowing it to be a potential target for treating AML.
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.
RohitKumar HG, Asha KR, Raghavan SC, Advi Rao GM DNA intercalative 4-butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline induces cell cycle arrest and apoptosis in leukemia cells. Cancer Chemother Pharmacol. 2015; 75(6):1121-33 [PubMed] Related Publications
PURPOSE: DNA intercalators are one of the interesting groups in cancer chemotherapy. The development of novel anticancer small molecule has gained remarkable interest over the last decade. In this study, we synthesized and investigated the ability of a tetracyclic-condensed quinoline compound, 4-butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline (BPTQ), to interact with double-stranded DNA and inhibit cancer cell proliferation. METHODS: Circular dichroism, topological studies, molecular docking, absorbance, and fluorescence spectral titrations were employed to study the interaction of BPTQ with DNA. Cytotoxicity was studied by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Further, cell cycle analysis by flow cytometry, annexin V staining, mitochondrial membrane potential assay, DNA fragmentation, and western blot analysis were used to elucidate the mechanism of action of BPTQ at the cellular level. RESULTS: Spectral, topological, and docking studies confirmed that BPTQ is a typical intercalator of DNA. BPTQ induces dose-dependent inhibitory effect on the proliferation of cancer cells by arresting cells at S and G2/M phase. Further, BPTQ activates the mitochondria-mediated apoptosis pathway, as explicated by a decrease in mitochondrial membrane potential, increase in the Bax:Bcl-2 ratio, and activation of caspases. CONCLUSION: These results confirmed that BPTQ is a DNA intercalative anticancer molecule, which could aid in the development of future cancer therapeutic agents.
Gonçalves C, Martins-Neves SR, Paiva-Oliveira D, et al. Sensitizing osteosarcoma stem cells to doxorubicin-induced apoptosis through retention of doxorubicin and modulation of apoptotic-related proteins. Life Sci. 2015; 130:47-56 [PubMed] Related Publications
AIMS: Osteosarcoma is the most common pediatric bone malignancy with high propensity to metastasize and relapse. Emerging evidence suggest that osteosarcoma is sustained by a subset of self-renewing cancer stem like cells (CSCs) relying on mechanisms to evade apoptosis and survive in response to drugs-induced DNA damage. We proposed to decipher the mechanisms underlying the resistance of CSCs to doxorubicin-induced apoptosis. MAIN METHODS: CSCs were isolated using a sphere-forming assay and tested for sensitivity to doxorubicin-induced apoptosis, using MTT cell viability and BrdU proliferation assays, TUNEL staining and caspases 3/7 activity. Bcl-2 family proteins were analyzed by Western blot. Doxorubicin uptake was determined by confocal microscopy and bioluminescence imaging. KEY FINDINGS: We showed that osteosarcoma sphere stem-like cells expressed the multidrug-related efflux transporters P-glycoprotein and BCRP and are highly resistant to doxorubicin-induced apoptosis. Conversely after exposure to doxorubicin, these cells displayed an up-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL with concomitant down-regulation of Bak and decreased caspase 3/7 activity. Inhibition of drug efflux transporters enhanced the cellular uptake of doxorubicin, being encompassed by an up-regulation the pro-apoptotic protein Bak and suppression of Bcl-2, favoring the commitment of CSCs towards apoptosis. SIGNIFICANCE: These results seemingly suggest that the high apoptotic threshold of CSCs to doxorubicin-induced cell dead stimuli is mainly dependent on the drug concentration reaching tumor cells that are governed by efflux transporter activity. Therefore, modulation of these transporters may be effective in potentiating the proapoptotic effects of doxorubicin, and emerges as an attractive strategy to sensitize osteosarcoma CSCs to chemotherapy.
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.
Xu J, Sun HY, Xiao FJ, et al. SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling. Biochem Biophys Res Commun. 2015; 460(2):409-15 [PubMed] Related Publications
SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-кB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM.
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.