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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

Web Resources: Apoptosis (2 links)

Latest Research Publications

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

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

Related: Lung Cancer Mitochondrial Mutations in Cancer

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.

Related: Leukemia Mitochondrial Mutations in 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.

Related: Breast Cancer

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.

Related: MicroRNAs

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.

Related: Lung Cancer Paclitaxel

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.

Related: Bone Cancers MMP9: matrix metallopeptidase 9 VEGFA

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.

Related: Acute Myeloid Leukemia (AML) Mitochondrial Mutations in Cancer

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

Related: Non-Small Cell Lung Cancer Cisplatin Lung Cancer Paclitaxel AKT1 MTOR

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

Related: Breast Cancer Oxaliplatin Docetaxel

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

Related: Breast Cancer

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

Related: Breast Cancer Trastuzumab (Herceptin)

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

Related: CASP3 Melanoma

Lopez J, Tait SW
Mitochondrial apoptosis: killing cancer using the enemy within.
Br J Cancer. 2015; 112(6):957-62 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Apoptotic cell death inhibits oncogenesis at multiple stages, ranging from transformation to metastasis. Consequently, in order for cancer to develop and progress, apoptosis must be inhibited. Cell death also plays major roles in cancer treatment, serving as the main effector function of many anti-cancer therapies. In this review, we discuss the role of apoptosis in the development and treatment of cancer. Specifically, we focus upon the mitochondrial pathway of apoptosis-the most commonly deregulated form of cell death in cancer. In this process, mitochondrial outer membrane permeabilisation or MOMP represents the defining event that irrevocably commits a cell to die. We provide an overview of how this pathway is regulated by BCL-2 family proteins and describe ways in which cancer cells can block it. Finally, we discuss exciting new approaches aimed at specifically inducing mitochondrial apoptosis in cancer cells, outlining their potential pitfalls, while highlighting their considerable therapeutic promise.

Related: Mitochondrial Mutations in Cancer Cancer Prevention and Risk Reduction Signal Transduction

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

Related: Gastrointestinal Stromal Tumors Signal Transduction Bortezomib Dasatinib (Sprycel)

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

Related: Soft Tissue Sarcomas Uterine Sarcoma

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

Related: Cutaneous T-cell lymphoma Skin Cancer

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

Related: Liver Cancer TP53

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

Related: Daunorubicin Acute Myeloid Leukemia (AML)

Münch C, Dragoi D, Frey AV, et al.
Therapeutic polo-like kinase 1 inhibition results in mitotic arrest and subsequent cell death of blasts in the bone marrow of AML patients and has similar effects in non-neoplastic cell lines.
Leuk Res. 2015; 39(4):462-70 [PubMed] Related Publications
Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML.

Related: Acute Myeloid Leukemia (AML)

Kim K, Yeo SG
Extracellular chaperonin 10 augments apoptotic cell death induced by 5-fluorouracil in human colon cancer cells.
Tumori. 2014 Nov-Dec; 100(6):e230-5 [PubMed] Related Publications
AIMS AND BACKGROUND: The molecular mechanisms involved in resistance to 5-fluorouracil (5-FU) in colon cancer patients remain to be elucidated. The purpose of this study was to identify proteins associated with 5-FU resistance in colon cancer.
METHODS AND STUDY DESIGN: Proteins secreted from a 5-FU-resistant human colon cancer cell line (SNU-C4 5-FU 200) were analyzed by two-dimensional gel electrophoresis-based proteomics, and identified using matrix-associated laser desorption/ionization-mass spectroscopy analysis and SWISS-PROT database searches. The expression levels of candidate proteins were determined by Western blotting and cell proliferation was monitored by MTT assay.
RESULTS: Chaperonin 10 (cpn10) was secreted at a lower level by 5-FU-resistant cells compared to the non-resistant parent cell line. The proliferation of both the parent and 5-FU-resistant cell lines increased slightly when extracellular cpn10 alone was added. However, in the presence of 5-FU, cpn10 augmented 5-FU-induced apoptotic death in both cell lines. Cpn10 led to activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and a specific ERK 1/2 inhibitor, PD98059, completely inhibited cpn10-stimulated cell proliferation.
CONCLUSIONS: Our findings indicate that concurrent treatment with cpn10 and 5-FU warrants further investigation in an effort to overcome 5-FU resistance and enhance the efficacy of 5-FU therapy for colon cancer.

Related: Fluorouracil

Xiao YC, Yang ZB, Cheng XS, et al.
CXCL8, overexpressed in colorectal cancer, enhances the resistance of colorectal cancer cells to anoikis.
Cancer Lett. 2015; 361(1):22-32 [PubMed] Related Publications
Anoikis is a form of apoptosis which occurs when anchorage-dependent cells either show loss of adhesion or inappropriate adhesion. Only a few cancer cells that detach from the primary site of the tumor acquire the ability to resist anoikis and form metastasis. The mechanism underlying the resistance of colorectal cancer (CRC) cells to anoikis remains unclear. Interleukin-8 (alternatively known as CXCL8) is associated with CRC angiogenesis and progression. Here, we found that a high abundance of CXCL8 or TOPK strongly correlated with poor overall and disease-free survival of 186 patients with CRC. A combination of high CXCL8 and high TOPK expressions had the worst prognosis. We showed that CXCL8 expression was negatively correlated with anoikis in CRC cells. CXCL8 treatment enhanced the resistance of CRC cells to apoptosis, which was accompanied by the increase of TOPK, and the activation of AKT and ERK. Moreover, we demonstrated that the inhibition of either ERK or AKT by specific chemical inhibitors attenuated the CXCL8-mediated resistance to anoikis. Treatment with AKT inhibitor abolished the effects of CXCL8 on TOPK expression, suggesting that TOPK was downstream of AKT in the process of anoikis. Taken together, we demonstrated that CXCL8 is strongly implicated in the resistance of CRC cells to anoikis, and that the AKT, TOPK and ERK pathway may be a potential therapeutic target for CRC.

Related: Colorectal (Bowel) Cancer AKT1 Signal Transduction

Changchien JJ, Chen YJ, Huang CH, et al.
Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.
Toxicol Appl Pharmacol. 2015; 284(1):33-41 [PubMed] Related Publications
Although previous studies have revealed the anti-cancer activity of quinacrine, its effect on leukemia is not clearly resolved. We sought to explore the cytotoxic effect and mechanism of quinacrine action in human leukemia K562 cells. Quinacrine induced K562 cell apoptosis accompanied with ROS generation, mitochondrial depolarization, and down-regulation of BCL2L1 and BCL2. Upon exposure to quinacrine, ROS-mediated p38 MAPK activation and ERK inactivation were observed in K562 cells. Quinacrine-induced cell death and mitochondrial depolarization were suppressed by the p38MAPK inhibitor SB202190 and constitutively active MEK1 over-expression. Activation of p38 MAPK was shown to promote BCL2 degradation. Further, ERK inactivation suppressed c-Jun-mediated transcriptional expression of BCL2L1. Over-expression of BCL2L1 and BCL2 attenuated quinacrine-evoked mitochondrial depolarization and rescued the viability of quinacrine-treated cells. Taken together, our data indicate that quinacrine-induced K562 cell apoptosis is mediated through mitochondrial alterations triggered by p38 MAPK-mediated BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology MAP2K1 Mitochondrial Mutations in Cancer Signal Transduction

Fiocchetti M, Camilli G, Acconcia F, et al.
ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury.
J Steroid Biochem Mol Biol. 2015; 149:128-37 [PubMed] Related Publications
Besides other mechanism(s) 17β-estradiol (E2) facilitates neuronal survival by increasing, via estrogen receptor β (ERβ), the levels of neuroglobin (NGB) an anti-apoptotic protein. In contrast, E2 could exert protective effects in cancer cells by activating apoptosis when the ERβ level prevails on that of ERα as in colon cancer cell lines. These apparently contrasting results raise the possibility that E2-induced NGB up-regulation could regulate the ERβ activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in non-neuronal cells. Here, human colorectal adenocarcinoma cell line (DLD-1) that only expresses ERβ and HeLa cells transiently transfected with ERβ encoding vector has been used to verify this hypothesis. In addition, neuroblastoma SK-N-BE cells were used as positive control. Surprisingly, E2 also induced NGB up-regulation, in a dose- and time-dependent manner, in DLD-1 cells. The ERβ-mediated activation of p38/MAPK was necessary for this E2 effect. E2 induced NGB re-allocation in mitochondria where, subsequently to an oxidative stress injury (i.e., 100μM H2O2), NGB interacted with cytochrome c preventing its release into the cytosol and the activation of an apoptotic cascade. As a whole, these results demonstrate that E2-induced NGB up-regulation could act as an oxidative stress sensor, which does not oppose to the pro-apoptotic E2 effect in ERβ-containing colon cancer cells unless a rise of oxidative stress occurs. These results support the concept that oxidative stress plays a critical role in E2-induced carcinogenesis and further open an important scenario to develop novel therapeutic strategies that target NGB against E2-related cancers.

Related: Mitochondrial Mutations in Cancer

Li M, Ma Y, Huang P, et al.
Lentiviral DDX46 knockdown inhibits growth and induces apoptosis in human colorectal cancer cells.
Gene. 2015; 560(2):237-44 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the leading causes of cancer related deaths worldwide. RNA helicases have been widely implicated in various types of cancer development. DDX46 belongs to the DEAD box family of RNA helicases, which are involved in the regulation of secondary RNA structures. The expression pattern of DDX46 in cancer tissues and the role of DDX46 in CRC progression have not been determined. In this study, we detected DDX46 protein expression in human CRC and adjacent tissues using immunohistochemistry. Our results showed that 87.04% of the columnar adenocarcinoma cases displayed high levels of focal nuclear DDX46 staining, and DDX46 protein expression was strongly increased in CRC tissues compared to adjacent tissues. Next, DDX46 RNAi lentivirus (DDX46-RNAi-LV) was used to silence the expression of DDX46 in the human colon carcinoma cells. Cells treated with the DDX46-RNAi-LV exhibited markedly reduced cell proliferation assessed by the MTT assay and visualized colony formation. Moreover, DDX46 silencing resulted in apoptotic induction via increased expression of cleaved caspase-3 and PARP. These results indicate that DDX46 is critical for CRC cell proliferation and is a potential therapeutic target for CRC treatment.

Related: Colorectal (Bowel) Cancer

Harati K, Slodnik P, Chromik AM, et al.
Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells.
Anticancer Res. 2015; 35(2):767-74 [PubMed] Related Publications
BACKGROUND/AIM: Metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin have been proven effective in fewer than 30% of all cases disseminated of fibrosarcoma. Elderly patients with cardiac disease are not suitable for systemic chemotherapy with doxorubicin. We therefore tested the apoptotic effects of the natural and well-tolerated compound resveratrol on human fibrosarcoma cells (HT1080).
MATERIALS AND METHODS: Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarrays.
RESULTS: Application of resveratrol induced apoptotic cell death and significantly reduced proliferation of HT1080 cells. Correspondingly, expression of apoptosis-associated genes was altered in microarray analysis.
CONCLUSION: This in vitro study demonstrates the anticancer activity of resveratrol against human fibrosarcoma cells. These results provide experimental support for in vivo trials assessing the effect of the natural polyphenol resveratrol.

Klemke CD, Feoktistova M, Leverkus M
Silencing autocrine death: a ubiquitin ligase that blocks activation-induced cell death in cutaneous T-cell lymphoma.
J Invest Dermatol. 2015; 135(3):662-5 [PubMed] Related Publications
Cutaneous T-cell lymphoma (CTCL) tumor cells lack the ability of activated T cells to undergo TCR/CD3-mediated activation-induced cell death (AICD). In this issue, the study reported by Wu et al. demonstrates that c-CBL (Casitas B-lineage Lymphoma proto-oncogene) is overexpressed in CTCL. When CTCL cells lose c-CBL, AICD is enhanced. Furthermore, combination therapy with methotrexate (a known demethylating agent for the CD95 gene) in combination with the loss of c-CBL increases CTCL cell death. Therefore, inhibition of c-CBL could represent a method of sensitizing lymphoma cells to enhance AICD. Armed with their novel data, the investigators envision combination therapies that target c-CBL to reactivate AICD in the malignant T cells whenever responsiveness to TCR/CD3 signaling is retained.

Related: Cutaneous T-cell lymphoma Skin Cancer

Smith AM, Little EB, Zivanovic A, et al.
Targeting survivin with YM155 (Sepantronium Bromide): a novel therapeutic strategy for paediatric acute myeloid leukaemia.
Leuk Res. 2015; 39(4):435-44 [PubMed] Related Publications
Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 μM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation.

Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology BIRC5

Stefanou DT, Bamias A, Episkopou H, et al.
Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer.
PLoS One. 2015; 10(2):e0117654 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.

Related: Carboplatin Ovarian Cancer

Di Bartolomeo S, Agostini A, Spinedi A
Differential apoptotic effect and metabolism of N-acetylsphingosine and N-hexanoylsphingosine in CHP-100 human neurotumor cells.
Biochem Biophys Res Commun. 2015; 458(3):456-61 [PubMed] Related Publications
The cytotoxic effects of N-acetylsphingosine (C2-Cer) and N-hexanoylsphingosine (C6-Cer) were compared together with their specific intracellular accumulation profiles and metabolism in human CHP-100 neuroepithelioma cells. The two short-chain ceramides, administered in the culture medium at an equimolar concentration, evoked a differential apoptotic response, with C6-Cer showing markedly more cytotoxic than C2-Cer. Apoptosis, that was suppressed in both cases by inhibition of caspase-9, but not of caspase-8, associated with a higher intracellular accumulation of C6-Cer over C2-Cer, notwithstanding C6-Cer was actively metabolized by direct glucosylation or by conversion to natural ceramide via the sphingosine salvage pathway, whereas C2-Cer was apparently metabolically inhert. C2-Cer cytotoxicity was markedly enhanced by increasing its concentration in the culture medium, and this response associated with a higher intracellular accumulation of this compound, in the absence of any natural ceramide elevation. These results support the notion that the differential apoptotic effect evoked by C2-Cer and C6-Cer in CHP-100 cells is driven by their differential intracellular accumulation profiles, but not by their differential property to generate natural ceramide via the sphingosine salvage pathway.

Chen ZF, Qin QP, Qin JL, et al.
Stabilization of G-quadruplex DNA, inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II) complexes with oxoisoaporphine.
J Med Chem. 2015; 58(5):2159-79 [PubMed] Related Publications
Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.

Related: Cancer Prevention and Risk Reduction

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