Apoptosis
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"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).

EI-Emshaty HM, Saad EA, Toson EA, et al.
Apoptosis and cell proliferation: correlation with BCL-2 and P53 oncoprotein expression in human hepatocellular carcinoma.
Hepatogastroenterology. 2014 Jul-Aug; 61(133):1393-401 [PubMed] Related Publications
BACKGROUND/AIM: Occurrence and biological characteristics of tumors are related not only to over-proliferation of carcinoma cells but also to decrease of apoptosis. The present study was suggested to evaluate the correlation between P53 and Bcl-2 oncoprotein expression with apoptosis and cell proliferative activity in HCC patients.
METHODOLOGY: P53 and Bcl-2 protein expression were estimated in the sera and in liver tissues of 45 HCC cases using ELISA and immunohistochemistry. Apoptosis was estimated as apoptotic index (AI) and cell proliferative activity was detected using AgNORs.
RESULTS: Serum p53 antigen in HCC patients (0.46±0.331ng/ml) showed significant elevation than healthy individuals (0.24±0.11ng/ml, p<0.05). P53 protein was immunostained in 41% of HCC; 37.5% of these positive cases were in diffuse pattern representing the mutant p53. Serum Bcl-2 was elevated in HCC cases (50.28±25.83u/ ml) than healthy individuals (26.65±8.63u/ml, p<0.05). Bcl-2 was immunohistochemically localized in 35.9% of HCC and the positivity was inversely proportional with the histological grade (47.4%, 25%, 25% in grade I,II,III respectively). Bcl-2 showed a positive linear correlation with p53 in the sera of carcinoma patients (p<0.05).
CONCLUSION: Bcl-2 may play a role in hepatocarcinogenesis as an inhibitor of apoptosis. However, a positive linear correlation was found between bcl-2 and p53 suggesting that bcl-2/p53 co-expression pattern may be of value in the development of more effective medical therapies in HCC.

Related: Liver Cancer TP53


Yunqiao L, Vanke H, Jun X, Tangmeng G
MicroRNA-206, down-regulated in hepatocellular carcinoma, suppresses cell proliferation and promotes apoptosis.
Hepatogastroenterology. 2014 Jul-Aug; 61(133):1302-7 [PubMed] Related Publications
BACKGROUND/AIMS: MicroRNA-206 has been proven down-regulated in many human malignancies and correlated with tumor progression. However, the expression and functions of miR-206 in hepatocellular carcinoma (HCC) are still unclear. The aim of this study was to explore the effects of miR-206 in HCC tumorigenesis and development.
METHODOLOGY: The expression levels of miR-206 were quantified by qRT-PCR in 147 surgically resected HCC and matched adjacent non-cancerous tissues, and correlated with clinicopathological factors. MTT, flow cytometric assay, and Transwell invasion and migration assays were used to test the proliferation, apoptosis, invasion, and migration of HepG2 HCC cells transfected with miR-206 mimics or negative control (NC) RNA-oligonucleotides.
RESULTS: MiR-206 expression was significantly downregulated in HCC compared with matched non-cancerous liver tissues. Low level of miR-206 was associated with poor tumor differentiation, multiple tumor nodes, lymph node metastasis, and advanced TNM stage. In addition, transfection of miR-206 mimics in HepG2 cells was able to reduce cell proliferation, invasion, and migration, and promote cell apoptosis.
CONCLUSIONS: These findings demonstrate that miRNA-206 could not only be useful as a novel biomarker but also serve as a potential target for gene therapy of HCC.

Related: Liver Cancer MicroRNAs


Yang P, Tuo L, Wu Q, Cao X
Licochalcone-A sensitizes human esophageal carcinoma cells to TRAIL-mediated apoptosis by proteasomal degradation of XIAP.
Hepatogastroenterology. 2014 Jul-Aug; 61(133):1229-34 [PubMed] Related Publications
BACKGROUND/AIMS: Esophageal carcinoma is one of the most aggressive human cancers, and novel treatment modality is required. Although expressing adequate levels of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, significant proportion of esophageal cancer cells exhibit resistance to the cytotoxic effect of this ligand. Licochalcone-A (LA), a flavonoid present in a variety of edible plants, exhibits a wide spectrum of pharmacologic properties such as anticancer, antioxidant, and anti-inflammatory activities.
METHODOLOGY: Eca109 and TE1 cells were cultured and transfected, then their viability was detected using MTT assay. Immunoprecipitation and immunoblotting analysis and RT-PCR analysis were also performed.
RESULTS: In this study, we found that LA synergistically caused the TRAIL-induced apoptosis in Eca109 and TE1 cells. Such potentiation was achieved through inhibiting Akt activation and promoting proteasomal degradation of X-linked Inhibitor of Apoptosis Protein (XIAP) which mediated the survival signals and allow the cells to escape from apoptosis in various human cancers.
CONCLUSIONS: The combination of TRAIL and LA might be a novel therapeutic strategy for esophageal carcinoma patients who fail to respond to standard chemotherapy.

Related: Cancer of the Esophagus Esophageal Cancer AKT1 TNFSF10


Tanagornmeatar K, Chaotham C, Sritularak B, et al.
Cytotoxic and anti-metastatic activities of phenolic compounds from Dendrobium ellipsophyllum.
Anticancer Res. 2014; 34(11):6573-9 [PubMed] Related Publications
BACKGROUND/AIM: Phenolic compounds isolated from Dendrobium ellipsophyllum Tang & Wang (Orchidaceae) have been shown to possess potential pharmacological activity; however, their anticancer as well as anti-metastasis activities are largely unknown. The aim of the present study was to isolate active compounds from D. ellipsophyllum and to explore the possible effects of phenolic compounds isolated from the plant for cytotoxic as well as anti-metastatic properties.
MATERIALS AND METHODS: The compounds were isolated by using chromatographic techniques including silica gel and Sephadex LH20. Each of the isolates was evaluated for their cytotoxicity on H292 human lung cancer cell lines by 2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. The cytotoxic compounds were further evaluated for apoptosis-inducing and anoikis-sensitizing effects.
RESULTS: Ten phenolic compounds were isolated, 5,7-dihydroxy-chromen-4-one (1:); 4,5-dihydroxy-2,3-dimethoxy-9,10-dihydrophenanthrene (2:); moscatilin (3:), 4,4'-dihydroxy-3,5-dimethoxybibenzyl (4:); 4,5,4'-trihydroxy-3,3'-dimethoxybibenzyl (5:); (2S)-homoeriodictyol (6:); (2S)-eriodictyol (7:); chrysoeriol (8:); phloretic acid (9:); and luteolin (10:). Compounds 4:, 5:, 8: and 10: exhibited appreciable cytotoxic activity with 50% inhibitory concentration values less than 250 μM. These compounds also showed potential apoptosis induction and anoikis-sensitizing effect at non-toxic concentrations.
CONCLUSION: Compounds 4:, 5:, 8: and 10: are responsible for cytotoxic and anti-metastatic activities of D. ellipsophyllum.


Wang X, Goldstein D, Crowe PJ, Yang JL
Impact of STAT3 inhibition on survival of osteosarcoma cell lines.
Anticancer Res. 2014; 34(11):6537-45 [PubMed] Related Publications
BACKGROUND/AIM: Osteosarcoma is often a fatal malignancy. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. We aimed to investigate the effect and potential molecular mechanisms of STAT3 inhibition on osteosarcoma.
MATERIALS AND METHODS: STAT3 inhibitor S3I-201 was investigated in six osteosarcoma cell lines. Crystal violet colorimetric, clonogenic, cleaved caspase-3 assays and western blot were performed to measure the effect and mechanisms of STAT3 inhibition.
RESULTS: All osteosarcoma cell lines expressed phosphorylated STAT3. Anti-proliferative effects of S3I-201 were dose- and time-dependent. S3I-201 also inhibited colony-formation and induced apoptosis through the caspase cleavage pathway. Finally, molecular mechanism studies suggested that down-regulation of STAT3 phosphorylation and downstream STAT3-target genes such as cyclin D1 and survivin may contribute to S3I-201-mediated anti-proliferation and apoptosis.
CONCLUSION: Inhibition of STAT3 signalling suppressed osteosarcoma cell growth and induced apoptosis, and indicated that STAT3 targeted-therapy may have therapeutic potential in osteosarcoma.

Related: Bone Cancers Osteosarcoma STAT3


Nagahara Y, Nagahara K
N-(2-amino-5-chlorobenzoyl)benzamidoxime derivatives inhibit human leukemia cell growth.
Anticancer Res. 2014; 34(11):6521-6 [PubMed] Related Publications
BACKGROUND/AIM: Amidoxime derivatives have been previously reported to have potent anti-microbial and anti-tumor activity. Little is known about the tumor cell growth-inhibition mechanism of amidoximes, especially benzamidoxime derivatives. Herein we determined the effects of N-(2-amino-5-chlorobenzoyl)benzamidoxime analogs on mammalian cancer cells.
MATERIALS AND METHODS: We synthesized four chloride-substituted benzamidoxime analogs from the original benzamidoxime to investigate their anticancer cell activity using the Jurkat T-cell lymphoma cell line and the human leukemia cell line HL-60RG.
RESULTS: All amidoxime derivatives inhibited Jurkat and HL-60RG cell viability dose-dependently. Benzamidoximes tended to damage HL-60RG cells to a greater extent compared to Jurkat cells. Benzamidoximes with chloride substitutes caused a strong decrease in cell growth, and this cell growth attenuation was transient at 5 μM (below the half-maximal inhibitory concentration, IC50) but long-lasting at 10 μM (greater than the IC50).
CONCLUSION: Benzamidoxime derivatives caused a transient cell-cycle delay at a low dose and cell death at a high dose.

Related: Leukemia


Sakai C, Arai M, Tanaka S, et al.
Effects of arsenic compounds on growth, cell-cycle distribution and apoptosis of tretinoin-resistant human promyelocytic leukemia cells.
Anticancer Res. 2014; 34(11):6489-94 [PubMed] Related Publications
BACKGROUND/AIM: The effects of inorganic and organic arsenicals on proliferation, cell-cycle distribution, and apoptosis of all-transretinoic acid (ATRA)-resistant human promyelocytic leukemia HL-60 (HL-60-R2) cells were herein investigated.
MATERIALS AND METHODS: Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell-cycle distribution and apoptotic cells were analyzed by flow cytometry.
RESULTS: The 50% inhibitory concentrations (IC50 values) for As2O3 against proliferation of HL-60 and HL-60-R2 cells were 12.2 and 7.2 μM, while those for arsenate were >200 and 62.1 μM, respectively. In contrast, organic methylarsinic acid, dimethylarsonic acid, trimethylarsine oxide, and tetramethylarsonium did not exert any inhibitory effects even at 200 μM. As2O3 and arsenate increased the proportion of apoptotic cells dose-dependently at a concentration range of 5-200 μM. As2O3 did not activate caspase 3/7 in HL-60 and HL-60-R2 cells.
CONCLUSION: As2O3 and arsenate inhibit cell proliferation, affect cell-cycle distribution, and induce apoptosis of ATRA-resistant HL-60-R2 cells. The apoptosis-inducing mechanism appears not to be mediated through caspase3/7.

Related: CASP3


Jarząb A, Grabarska A, Kiełbus M, et al.
Osthole induces apoptosis, suppresses cell-cycle progression and proliferation of cancer cells.
Anticancer Res. 2014; 34(11):6473-80 [PubMed] Related Publications
BACKGROUND: The aim of the present study was to determine the effects of osthole on cell proliferation and viability, cell-cycle progression and induction of apoptosis in human laryngeal cancer RK33 and human medulloblastoma TE671 cell lines.
MATERIALS AND METHODS: Cell viability was measured by means of the MTT method and cell proliferation by the 5-bromo-2-deoxyuridine (BrdU) incorporation assay. Cell-cycle progression was determined by flow cytometry, and induction of apoptosis by release of oligonucleosomes to the cytosol. The gene expression was estimated by a quantitative polymerase chain reaction (qPCR) method. High-performance counter-current chromatography (HPCCC) was applied for isolation of osthole from fruits of Mutellina purpurea.
RESULTS: Osthole decreased proliferation and cell viability of cancer cells in a dose-dependent manner. The tested compound induced apoptosis, increased the cell numbers in G1 and decreased cell number in S/G2 phases of the cell cycle, differentially regulating CDKN1A and TP53 gene expression depending on cancer cell type.
CONCLUSION: Osthole could be considered as a potential compound for cancer therapy and chemoprevention.

Related: CDKN1A Cancer of the Larynx Laryngeal Cancer - Molecular Biology Childhood Medulloblastoma / PNET TP53


Lachaier E, Louandre C, Godin C, et al.
Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors.
Anticancer Res. 2014; 34(11):6417-22 [PubMed] Related Publications
BACKGROUND/AIM: Ferroptosis is a recently identified form of regulated necrosis that can be experimentally induced in cancer cells with the chemical inducer erastin. Recently, we identified sorafenib, an inhibitor of oncogenic kinases, as an inducer of ferroptosis in hepatocellular carcinoma cells. Whether sorafenib is able to exert its ferroptotic activity in cancer cells originating from other tissues is presently unclear.
MATERIALS AND METHODS: We compared the levels of ferroptosis induced by sorafenib with those induced by the reference compound erastin in a panel of ten human cell lines originating from various tissues.
RESULTS: Sorafenib induced ferroptosis in different cancer cell lines. We found a positive correlation between the ferroptotic potency of sorafenib and erastin. Compared to other kinase inhibitors, sorafenib is the only drug that displays ferroptotic efficacy.
CONCLUSION: The findings establish sorafenib as the first clinically-approved anticancer drug that can induce ferroptosis.

Related: Cancer Prevention and Risk Reduction Sorafenib (Nexavar)


Nicolin V, Fancellu G, Valentini R
Effect of tanshinone II on cell growth of breast cancer cell line type MCF-7 and MD-MB-231.
Ital J Anat Embryol. 2014; 119(1):38-43 [PubMed] Related Publications
Breast cancer is the most common form of cancer in women and the leading cause of cancer death in American women, with over 207,090 new cases of invasive breast cancer in women and about 39,840 deaths from breast cancer in 2010. Current therapies for breast cancer usually have variable effectiveness with high toxicity to normal tissues, and breast tumours often develop metastasis and drug resistance. Therefore, searching for effective regimens with minimal side effects remains the top priority in breast cancer research. The objectives of this study were to evaluate the effects of tanshinone II from a Chinese herb, Salvia miltiorrhiza, on the growth of breast cancer cells type MCF-7 and MDA-MB-231.

Related: Breast Cancer


Liu BX, Zhou JY, Li Y, et al.
Hederagenin from the leaves of ivy (Hedera helix L.) induces apoptosis in human LoVo colon cells through the mitochondrial pathway.
BMC Complement Altern Med. 2014; 14:412 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer has become one of the leading cause of cancer morbidity and mortality throughout world. Hederagenin, a derivative of oleanolic acid isolated from the leaves of ivy (Hedera helix L.), has been shown to have potential anti-tumor activity. The study was conducted to evaluate whether hederagenin could induce apoptosis of human colon cancer LoVo cells and explore the possible mechanism.
METHODS: MTT assay was used for evaluating cell viability while Annexin V-FITC/PI assay and Hoechst 33342 nuclear stainining were used for the determination of apoptosis and mitochondrial membrane potential. DCFH-DA fluorescence staining and flow cytometry were used to measure ROS generation. Real-time PCR and western blot analysis were performed for apoptosis-related protein expressions.
RESULTS: MTT assay showed that hederagenin could significantly inhibit the viability of LoVo cells in a concentration-dependent and time-dependent manner by IC50 of 1.39 μM at 24 h and 1.17 μM at 48 h. The apoptosis ratio was significantly increased to 32.46% and 81.78% by the induction of hederagenin (1 and 2 μM) in Annexin V-FITC/PI assay. Hederagenin could also induce the nuclear changes characteristic of apoptosis by Hoechst 33342 nuclear stainining under fluorescence microscopy. DCFH-DA fluorescence staining and flow cytometry showed that hederagenin could increase significantly ROS generation in LoVo cells. Real-time PCR showed that hederagenin induced the up-regulation of Bax and down-regulation of Bcl-2, Bcl-xL and Survivin. Western blotting analysis showed that hederagenin decreased the expressions of apoptosis-associated proteins Bcl-2, procaspase-9, procaspase-3, and polyADP- ribosepolymerase (PARP) were increased, while the expressions of Bax, caspase-3, caspase-9 were increased. However, there was no significant change on caspase-8.
CONCLUSIONS: These results indicated that the disruption of mitochondrial membrane potential might contribute to the apoptosis of hederagenin in LoVo cells. Our findings suggested that hederagenin might be a promising therapeutic candidate for human colon cancer.

Related: CASP3 Mitochondrial Mutations in Cancer


Currò M, Montalto AS, Impellizzeri P, et al.
CO(2) pneumoperitoneum induces in vitro hypoxic response culminating in apoptosis of human neuroblastoma cells.
J Biol Regul Homeost Agents. 2014 Jul-Sep; 28(3):497-506 [PubMed] Related Publications
The ablative role of minimally invasive surgery (MIS) in neuroblastoma (NB) is still controversial due to the possible CO₂ pneumoperitoneum side-effects on tumor aggressiveness. It is known that CO₂ produces hypoxic condition with changes in tumor microenvironment influencing cell functions. Here we investigated whether CO₂ exposure affects the transcription factor HIF-1α and the apoptotic signalling pathway in SH-SY5Y NB cells. SH-SY5Y cells were exposed to a pressure of 15 mmHg CO₂ (100%) for 4 h (T0) and then moved to normal condition for 24 h (T₂₄). In control and CO₂ -exposed cells, we analyzed the mRNA levels and DNA binding activity of HIF-1α. We also evaluated the proliferative activity and cell viability as well as caspase-9/3 cleavage and nuclear fragmentation. A significant increase in HIF- 1α activation was observed in SH-SY5Y cells exposed to CO₂ compared to control cells. CO₂ treatment also decreased the proliferation rate and the percentage of viable cells. In addition, the expression and cleavage of caspase-9 and -3 were significantly increased in NB cells exposed to CO₂. These data correlated with apoptotic feature observed in CO₂ -treated NB cells. Our findings show that CO₂ -induced hypoxic condition exerts cytotoxic effects on NB cells by eliciting mitochondrial apoptotic pathway and thereby improving the understanding of the possible clinical impact of CO₂ pneumoperitoneum on NB behaviour.

Related: CASP3 HIF1A Neuroblastoma


Shebaby WN, Mroueh M, Bodman-Smith K, et al.
Daucus carota pentane-based fractions arrest the cell cycle and increase apoptosis in MDA-MB-231 breast cancer cells.
BMC Complement Altern Med. 2014; 14:387 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Daucus carota L.ssp.carota (wild carrot), an herb used in folk medicine worldwide, was recently demonstrated to exhibit anticancer activity. In this study we examined the anticancer effect of Daucus carota oil extract (DCOE) fractions on the human breast adenocarcinoma cell lines MDA-MB-231 and MCF-7 and clarified the mechanism of action.
METHODS AND RESULTS: Using the WST assay, the pentane fraction (F1) and 1:1 pentane:diethyl ether fraction (F2) were shown to possess the highest cytotoxicity against both cell lines. Flow cytometric analysis revealed that both fractions induced the accumulation of cells in the sub-G1 phase, increase in apoptotic cell death and chromatin condensation. The increase in apoptosis in response to treatment was also apparent in the increase in BAX and the decrease in Bcl-2 levels as well as the proteolytic cleavage of both caspase-3 and PARP as revealed by Western blot. Furthermore, treatment of MDA-MB-231 cells with either fraction significantly reduced the level of phosphorylated Erk but did not show any effect on phosphorylated Akt. The combined treatment with a potent PI3K inhibitor (wortmannin) and F1 or F2 fraction had a synergistic inhibitory effect on cell survival which shows that these two drugs work on different pathways.
CONCLUSIONS: These results suggest that the pentane-based fractions of DCOE possess potential anti-cancer activity that is mainly mediated through the Erk pathway.

Related: Breast Cancer CASP3 AKT1


Koschny R, Boehm C, Sprick MR, et al.
Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex.
J Neuropathol Exp Neurol. 2014; 73(11):1034-46 [PubMed] Related Publications
A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.

Related: TNFSF10 Bortezomib


Scheit K, Bauer G
Synergistic effects between catalase inhibitors and modulators of nitric oxide metabolism on tumor cell apoptosis.
Anticancer Res. 2014; 34(10):5337-50 [PubMed] Related Publications
Inhibitors of catalase (such as ascorbate, methyldopa, salicylic acid and neutralizing antibodies) synergize with modulators of nitric oxide (NO) metabolism (such as arginine, arginase inhibitor, NO synthase-inducing interferons and NO dioxygenase inhibitors) in the singlet oxygen-mediated inactivation of tumor cell protective catalase. This is followed by reactive oxygen species (ROS)-dependent apoptosis induction. TGF-beta, NADPH oxidase-1, NO synthase, dual oxidase-1 and caspase-9 are characterized as essential catalysts in this process. The FAS receptor and caspase-8 are required for amplification of ROS signaling triggered by individual compounds, but are dispensable when the synergistic effect is established. Our findings explain the antitumor effects of catalase inhibitors and of compounds that target NO metabolism, as well as their synergy. These data may have an impact on epidemiological studies related to secondary plant compounds and open new perspectives for the establishment of novel antitumor drugs and for the improvement of established chemotherapeutics.

Related: Cancer Prevention and Risk Reduction


Zhao X, Yuan Y, Zhang Z, et al.
Effects of shRNA-silenced livin and survivin on lung cancer cell proliferation and apoptosis.
J BUON. 2014 Jul-Sep; 19(3):757-62 [PubMed] Related Publications
PURPOSE: To evaluate the effects of short hairpin RNA (shRNA)-mediated silencing of livin and survivin on the proliferation and apoptosis of A549 lung cancer cells.
METHODS: We designed and constructed the eukaryotic expression vectors pSilencer-livin and pSilencer-survivin which contain the Livin and Survivin genes, respectively, and transfected them into liposome-combined lung cancer A549 cells. The cells were then divided into the blank control, plasmid control, Livin, Survivin, and co-transfected groups. Real-time quantitative PCR (qRT-PCR) and Western blot assay were used to determine the mRNA and protein expression levels of Livin and Survivin. The MTT assay was used to evaluate the changes in cell proliferation. The TUNEL assay was used to evaluate the apoptotic rate.
RESULTS: The shRNA eukaryotic expression vectors of Livin and Survivin were successfully constructed. The mRNA and protein expression of Livin and Survivin were significantly lower in the co-transfected group than in the control groups (p<0.05) . At 48, 60, and 72 hrs after transfection, the cell growth inhibition rate was significantly higher in the co-transfected group than in the single- transfected group (p<0.05) . At 48 hrs after transfection, the apoptotic rate significantly increased (p<0.05) .
CONCLUSION: Co-silencing of Livin and Survivin can effectively inhibit the cell proliferation and apoptosis of lung cancer cells.

Related: Lung Cancer BIRC5


Liu ML, Zhang SJ
Effects of resveratrol on the protein expression of survivin and cell apoptosis in human gastric cancer cells.
J BUON. 2014 Jul-Sep; 19(3):713-7 [PubMed] Related Publications
PURPOSE: This study aimed to investigate the effects of resveratrol on cell proliferation, apoptosis and protein expression of survivin in human gastric cancer (SGC7901) cell line.
METHODS: SGC7901 cell proliferation and G0/G1 phase of the cell cycle induced by resveratrol (treatment group) and phosphate buffer solution (PBS) (control group) were assessed by flow cytometry. In addition, protein expression of survivin was assessed by immunohistochemistry after treatment with resveratrol.
RESULTS: SGC7901 cell apoptosis rates were 0.00% and 3.45% in the control and treatment groups, respectively. Furthermore, cell cycles were significantly changed in the resveratrol group; for example, the proportion of the G0/G1 phase increased, whereas the proportion of the S and G2/M phases decreased. Survivin protein expression was significantly reduced (p<0.01) in the treatment group compared with that in the control group.
CONCLUSION: Resveratrol inhibited the proliferation of SGC7901 cancer cells by inducing cell apoptosis and down-regulating survivin expression.

Related: Stomach Cancer Gastric Cancer BIRC5


Wang Y, Kong WZ, Xing LH, Yang X
Effects and mechanism of suberoylanilide hydroxamic acid on the proliferation and apoptosis of human hepatoma cell line Bel-7402.
J BUON. 2014 Jul-Sep; 19(3):698-704 [PubMed] Related Publications
PURPOSE: To investigate the effects and mechanism of suberoylanilide hydroxamic acid (SAHA) on the proliferation and apoptosis of human hepatoma cell line Bel-7402.
METHODS: SAHA treatment and control groups were designed in this study. To observe the morphological characteristics and the inhibition of cell proliferation, we conducted confocal microscopy and methyl thiazolyl tetrazolium (MTT) assay, respectively. Changes in cell apoptosis and cell cycle were then determined by flow cytometry. Real-time polymerase chain reaction (RT-PCR) was also conducted to detect the mRNA expressions of p53, bcl-2 and bax genes. Caspase-3 protein activity was determined by spectrophotometry.
RESULTS: Cell proliferation in the SAHA treatment group could be inhibited in a time- and dose-dependent manner. FCM analysis showed that the early apoptosis rate in the SAHA treatment group increased significantly. Furthermore, cell cycle was arrested at the S phase. RT-PCR assay confirmed that SAHA could upregulate the mRNA expressions of p53 and bax genes. By comparison, SAHA could downregulate the mRNA expression of bcl-2. SAHA induced apoptosis by activating the caspase-3 pathway.
CONCLUSION: SAHA inhibited cell proliferation and promoted human hepatoma Bel-7402 cell apoptosis by affecting caspase-3 protein activity and mRNA expressions of p53, bcl-2 and bax genes.

Related: CASP3 Liver Cancer


Zhang Y, Lin A, Sui Q, et al.
Phosphorothioate modification of the TLR9 ligand CpG ODN inhibits poly(I:C)-induced apoptosis of hepatocellular carcinoma by entry blockade.
Cancer Lett. 2014; 355(1):76-84 [PubMed] Related Publications
Toll-like receptors (TLRs) play a crucial role in the innate immune response and subsequent induction of adaptive immune responses. Recently, it has been noted that TLRs on tumor cells are involved in tumor development, and several TLR agonists, such as the TLR3 agonist poly(I:C) and the TLR9 agonist CpG ODN, are being developed as vaccine adjuvants and cancer immunotherapeutics. In this study, we investigated whether combining poly(I:C) with a TLR9 agonist CpG ODN would result in a stronger anti-tumor effect on hepatocellular carcinoma cells (HCCs). Surprisingly, we found that simultaneous transfection of poly(I:C) and ODN M362 exhibited a lower pro-apoptotic effect on HCCs than transfection with poly(I:C) alone. Simultaneous co-transfection was accompanied by down-regulation of poly(I:C)-related innate receptors, pro-inflammatory cytokines and apoptotic genes induced by poly(I:C), indicating that ODN M362 blocked the activation of poly(I:C)-triggered intrinsic immune responses and cellular apoptosis. Further studies indicated that these effects were partly due to the phosphorothioate-modification of CpG ODN, which blocked the entry of poly(I:C) into tumor cells. This entry blockade was avoided by administering poly(I:C) after CpG ODN. Moreover, poly(I:C)-mediated pro-apoptotic effects were enhanced in vitro and in vivo by pre-treating HCC cells with CpG ODN. Our findings thus suggest that when combining poly(I:C) and CpG ODN for cancer therapy, these agents should be used in an alternating rather than simultaneous manner to avoid the blocking effect of phosphorothioate-modified TLR9 ligands.

Related: Liver Cancer


Obakan P, Arisan ED, Coker-Gurkan A, Palavan-Unsal N
Epibrassinolide-induced apoptosis regardless of p53 expression via activating polyamine catabolic machinery, a common target for androgen sensitive and insensitive prostate cancer cells.
Prostate. 2014; 74(16):1622-33 [PubMed] Related Publications
BACKGROUND: Epibrassinolide (EBR), is a member of the brassinosteroids (BR), has been shown as an apoptotic inducer in different cancer cell lines. We previously showed that EBR induced apoptosis by activating polyamine catabolic pathway, which lead to the accumulation of cytotoxic compounds such as hydrogen peroxide and aldehydes in LNCaP and DU 145 prostate cancer cells. However, we found that LNCaP prostate cancer cells expressing functional androgen receptor (AR) was found more sensitive to EBR than those with non-functional AR (DU 145 cells).
RESULTS: To better understand the apoptotic effect of EBR, we aimed to investigate the cellular responses in p53 null, PC3 prostate cancer cells. We showed that EBR induced mitochondria-mediated and caspase-dependent apoptosis in wt and p53 stable transfected PC3 cells, which suggesting that EBR-induced apoptosis regardless of p53 expression. In addition, inhibition of p53 by pifithrin-α orthe activation of Mdm2 by Nutlin-3 co-treatment did not alter EBR induced PARP cleavage. Furthermore, EBR treatment was also induced apoptosis in both LNCaP(wt p53) and DU 145 (mt p53)cells, respectively. These all findings verified that EBR-induced apoptosis regardless of p53 expression. The PA catabolic pathway was also altered in PC3 cells causing the generation of reactive oxygen species (ROS) and intracellular PA pool decrease. However, the silencing of spermidine-spermineacetyltransferase (SSAT), a key enzyme at polyamine catabolic machinery prevented the EBR-induced apoptosis.
CONCLUSIONS: Therefore, we concluded that EBR-induced apoptosis was mainly related with PA catabolic pathway and independent from p53 expression.

Related: Prostate Cancer Signal Transduction TP53


Koong LY, Watson CS
Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells.
Prostate. 2014; 74(16):1589-603 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Diethylstilbestrol (DES) and other pharmaceutical estrogens have been used at ≥ µM concentrations to treat advanced prostate tumors, with successes primarily attributed to indirect hypothalamic-pituitary-testicular axis control mechanisms. However, estrogens also directly affect tumor cells, though the mechanisms involved are not well understood.
METHODS: LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cell viability was measured after estradiol (E2) or DES treatment across wide concentration ranges. We then examined multiple rapid signaling mechanisms at 0.1 nM E2 and 1 µM DES optima including levels of: activation (phosphorylation) for mitogen-activated protein kinases, cell-cycle proteins, and caspase 3, necroptosis, and reactive oxygen species (ROS).
RESULTS: LAPC-4 cells were more responsive than PC-3 cells. Robust and sustained extracellular-regulated kinase activation with E2 , but not DES, correlated with ROS generation and cell death. c-Jun N-terminal kinase was only activated in E2-treated PC-3 cells and was not correlated with caspase 3-mediated apoptosis; necroptosis was not involved. The cell-cycle inhibitor protein p16(INK4A) was phosphorylated in both cell lines by both E2 and DES, but to differing extents. In both cell types, both estrogens activated p38 kinase, which subsequently phosphorylated cyclin D1, tagging it for degradation, except in DES-treated PC-3 cells.
CONCLUSIONS: Cyclin D1 status correlated most closely with disrupted cell cycling as a cause of reduced cell numbers, though other mechanisms also contributed. As low as 0.1 nM E2 effectively elicited these mechanisms, and its use could dramatically improve outcomes for both early- and late-stage prostate cancer patients, while avoiding the side effects of high-dose DES treatment.

Related: CASP3 Prostate Cancer


Bhoopathi P, Quinn BA, Gui Q, et al.
Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid.
Cancer Res. 2014; 74(21):6224-35 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Polyinosine-polycytidylic acid [pIC] is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and natural killer cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells (PDAC) but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC](PEI)) in PDAC and investigated its mechanism of action. [pIC](PEI) stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC](PEI) repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I, and NOXA. Phosphorylation of AKT was inhibited by [pIC](PEI) in PDAC, and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC](PEI) inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC](PEI) as an immunochemotherapy to treat pancreatic cancer.

Related: Cancer of the Pancreas Pancreatic Cancer


Wang Y, Chen D, Qian H, et al.
The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression.
Cancer Cell. 2014; 26(3):374-89 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
Splicing dysregulation is one of the molecular hallmarks of cancer. However, the underlying molecular mechanisms remain poorly defined. Here we report that the splicing factor RBM4 suppresses proliferation and migration of various cancer cells by specifically controlling cancer-related splicing. Particularly, RBM4 regulates Bcl-x splicing to induce apoptosis, and coexpression of Bcl-xL partially reverses the RBM4-mediated tumor suppression. Moreover, RBM4 antagonizes an oncogenic splicing factor, SRSF1, to inhibit mTOR activation. Strikingly, RBM4 expression is decreased dramatically in cancer patients, and the RBM4 level correlates positively with improved survival. In addition to providing mechanistic insights of cancer-related splicing dysregulation, this study establishes RBM4 as a tumor suppressor with therapeutic potential and clinical values as a prognostic factor.

Related: Non-Small Cell Lung Cancer Lung Cancer MTOR


Kim EY, Shin JY, Park YJ, Kim AK
Equol induces mitochondria-mediated apoptosis of human cervical cancer cells.
Anticancer Res. 2014; 34(9):4985-92 [PubMed] Related Publications
BACKGROUND/AIM: The present study aimed to investigate anticancer properties of equol and demonstrate its underlying mechanisms of action in human cervical cancer HeLa cells.
MATERIALS AND METHODS: Inhibition of cell viability was examined by 3-(4,5-dimethylthiazoly-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was evaluated by observation of apoptotic cell morphology, and an increase of annexin-V(+) cells. Western blotting was used to examine apoptosis-related proteins. Flow cytometry was used to measure mitochondrial membrane potential (MMP) and reactive oxygen species (ROS).
RESULTS: Equol treatment inhibited HeLa cell proliferation in dose- and time-dependent manner. Equol-induced apoptotic cell death was accompanied by the activation of caspases, and alteration of MMP and mitochondrial membrane proteins; equol also rapidly triggered ROS production. Pre-treatment with N-acetylcysteine blocked loss of MMP, caused increase of Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio, caspase-8 activation, and apoptosis induced by equol.
CONCLUSION: Equol is a potential anticancer agent against HeLa, with possible mechanisms involved in ROS generation and mitochondrial membrane alteration.

Related: Mitochondrial Mutations in Cancer Signal Transduction Cervical Cancer


Belkacemi L, Hebb MO
HSP27 knockdown produces synergistic induction of apoptosis by HSP90 and kinase inhibitors in glioblastoma multiforme.
Anticancer Res. 2014; 34(9):4915-27 [PubMed] Related Publications
BACKGROUND/AIM: The heat-shock proteins HSP27 and HSP90 perpetuate the malignant nature of glioblastoma multiforme (GBM) and offer promise as targets for novel cancer therapeutics. The present study sought to define synergistic antitumor benefits of concurrent HSP27-knockdown and the HSP90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) or, comparatively, the non-selective kinase inhibitor, staurosporine, in GBM cells.
MATERIALS AND METHODS: Dose-response relations were determined for 17-AAG and staurosporine in three GBM cell lines. HSP27-targeted siRNA was administered alone or in combination with subtherapeutic concentrations of each drug and cells were evaluated for viability, proliferation and apoptosis.
RESULTS: Adjuvant HSP27 knockdown with 17-AAG or staurosporine produced marked and synergistic decrease in GBM cell viability and proliferation, with robust elevation of apoptotic fractions and caspase-3 activation.
CONCLUSION: HSP27 knockdown confers potent chemosensitization of GBM cells. These novel data support the development of HSP-targeting strategies and, specifically, anti-HSP27 agents for the treatment of GBM.

Related: CASP3


Kim SH, Shin HY, Kim YS, et al.
Tunicamycin induces paraptosis potentiated by inhibition of BRAFV600E in FRO anaplastic thyroid carcinoma cells.
Anticancer Res. 2014; 34(9):4857-68 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to elucidate whether tunicamycin (TM) induces paraptosis as a cell death subroutine in anaplastic thyroid carcinoma (ATC) cells.
MATERIALS AND METHODS: 8505C, CAL62 and FRO cells were used. After treatment of TM, cell survival and morphology were investigated. The effect of the BRAF(V600E) inhibitor PLX4032 in combination with TM was evaluated.
RESULTS: In FRO cells, TM induced paraptosis characteristic of cytoplasmic vacuolation and endoplasmic reticulum (ER) swelling, which was not associated with caspase activation and ER stress. TM-induced paraptosis was ameliorated by pre-treatment with the translation inhibitor cycloheximide, while it was accelerated by pre-treatment with the proteasome inhibitor MG132. PLX4032 augmented TM-induced paraptosis.
CONCLUSION: TM induces paraptosis relevant to de novo protein synthesis and proteasomal activity, and inhibition of BRAF(V600E) potentiates TM-induced paraptosis in FRO cells harboring BRAF(V600E).

Related: BRAF gene Thyroid Cancer Vemurafenib (Zelboraf)


Ichihara H, Nakagawa S, Matsuoka Y, et al.
Nanotherapy with hybrid liposomes for colorectal cancer along with apoptosis in vitro and in vivo.
Anticancer Res. 2014; 34(9):4701-8 [PubMed] Related Publications
AIM: We examined the therapeutic effects of hybrid liposomes (HL) composed of L-α-dimyristylphosphati-dylcholine (DMPC) and polyoxyethylene (25) dodecyl ether (C12(EO)25) on the growth of human colorectal cancer (WiDr) cells in vitro and in vivo.
MATERIALS AND METHODS: HL composed of 95 mol% DMPC and 5 mol% C12(EO)25 were prepared by the sonication method and their therapeutic effects in xenograft mouse models of colorectal cancer liver metastases were examined in vivo.
RESULTS: The inhibitory effects of HL-25 on the growth of WiDr cells along with apoptosis were assessed in vitro. Remarkable inhibitory effects of HL-25 for the liver metastasis of colorectal cancer cells along with apoptosis were revealed on the basis of histological analysis. Prolonged survival was attained for the xenograft mouse model of colorectal cancer after treatment with HL-25 in vivo.
CONCLUSION: Therapeutic effects of HL-25 without any drugs on the liver metastasis of human colorectal cancer were obtained for the first time in vivo.

Related: Colorectal (Bowel) Cancer


Suzuki R, Kang Y, Li X, et al.
Genistein potentiates the antitumor effect of 5-Fluorouracil by inducing apoptosis and autophagy in human pancreatic cancer cells.
Anticancer Res. 2014; 34(9):4685-92 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
BACKGROUND: Although 5-fluorouracil (5-FU)-based combination chemotherapy (i.e. FOLFIRINOX) has demonstrated effectiveness against pancreatic cancer, novel therapeutic strategies must be developed to increase the therapeutic window of these cytotoxic agents. Genistein is a soy-derived isoflavone with pleiotropic biological effects that can enhance the antitumor effect of chemotherapeutic agents.
MATERIALS AND METHODS: To understand how genistein potentiates the antitumor effects of 5-FU, we examined apoptosis and autophagy in MIA PaCa-2 human pancreatic cancer cells and their derived xenografts. Apoptosis was evaluated using DNA fragmentation assays, and western blots of poly(ADP ribose)polymerase and caspase-3. Meanwhile, autophagy was evaluated using western blots of microtubule-associated protein light chain 3 (LC3)-I/II, fluorescent microscopy observation of green fluorescent protein-LC3B puncta formation, and acidic vesicular organelle formation using acridine orange staining. Tumors from animal treatment studies were examined for apoptosis and autophagy using the TdT-mediated dUTP nick-end labeling assay and immunohistochemical staining of LC3B, respectively.
RESULTS: We observed that genistein increased 5-FU-induced cell death through increased apoptosis, as well as autophagy. The increased autophagy was accompanied by decreased B-cell lymphoma 2 (Bcl2) and increased beclin-1 protein levels. Animal treatment studies supported these observations. The combination of 5-FU and genistein significantly reduced final xenograft tumor volume when compared to 5-FU-alone by inducing apoptosis as well as autophagy.
CONCLUSION: Genistein can potentiate the antitumor effect of 5-FU by inducing apoptotic as well as autophagic cell death. These results demonstrate the potential of genistein as an adjuvant therapeutic agent against pancreatic cancer.

Related: Fluorouracil Cancer of the Pancreas Pancreatic Cancer


Engel N, Falodun A, Kühn J, et al.
Pro-apoptotic and anti-adhesive effects of four African plant extracts on the breast cancer cell line MCF-7.
BMC Complement Altern Med. 2014; 14:334 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
BACKGROUND: Jatropha curcas (JCP1), Pyrenacantha staudtii (PS), Picralima nitida (ZI) and Jatropha gossypifolia (JCP2) are plants used in the African folklore for the treatment of various cancers.
METHODS: This study investigated the in vitro anticancer effects of the ethanol extracts against human epithelial MCF-7 breast cancer cells in a dose-dependent manner (1-50 μg/ml) by using cell cycle analysis, viability assay, annexin V/PI staining, TUNEL method and expression determination of apoptotic and adhesion relevant proteins. Adhesion processes were monitored by detachment via flow cytometry, β1-integrin expression and formation of the actin cytoskeleton.
RESULTS: The three extracts, termed PS, JCP1 and JCP2 at a concentration of 10 μg/ml induced cell death in MCF-7 breast cancer cells verified by high amounts of PI-positive cells in the cell cycle analysis, Annexin V/PI staining and DNA fragmentation measurements. In parallel cell detachment was accompanied by decreased β1- integrin expression and phosphorylation of the focal adhesion kinase at Tyr397. ZI extract was the exception by the increasing β1-integrin expression and strengthening the cortical actin cytoskeleton. However, all four plant extracts mediated strong anti-cancer properties with IC50 values between 23-38 μg/ml.
CONCLUSION: PS, JCP1 and JCP2 were found to be very active against MCF-7 cells by inducing anoikis and therefore possessing vast potential as medicinal drugs especially in estrogen receptor positive breast cancer treatment. ZI mediated their anti-cancer action by different signaling mechanisms which should be analyzed in future studies. Our results further supported the idea that medicinal plants can be promising sources of putative anticancer agents.

Related: ITGB1 Breast Cancer


Chao TT, Wang CY, Lai CC, et al.
TD-19, an erlotinib derivative, induces epidermal growth factor receptor wild-type nonsmall-cell lung cancer apoptosis through CIP2A-mediated pathway.
J Pharmacol Exp Ther. 2014; 351(2):352-8 [PubMed] Related Publications
Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.

Related: Non-Small Cell Lung Cancer CASP3 Lung Cancer AKT1 EGFR Erlotinib (Tarceva)


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