scholarly journals B4G2 Induces Mitochondrial Apoptosis by the ROS-Mediated Opening of Ca2+-Dependent Permeability Transition Pores

2015 ◽  
Vol 37 (3) ◽  
pp. 838-852 ◽  
Author(s):  
Nan Yao ◽  
Ying-Jie Li ◽  
Dong-Mei Zhang ◽  
Dao-Lu Liu ◽  
Ming-Kuen Tang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Intracellular Calcium ◽  
Cell Lines ◽  
Permeability Transition ◽  
Mitochondrial Apoptosis ◽  
Mitochondrial Potential ◽  
Pre Treatment ◽  
Permeability Transition Pores ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Background/Aims: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. At present, only sorafenib is approved to treat HCC. In this study, we found that a 23-hydroxybetulinic acid derivative, B4G2, exhibited potent antiproliferative activity in HCC cell lines. Methods: We used four HCC cell lines (HepG2, HepG2/ADM, Hep3B and Bel-7402) to evaluate the anti-tumour activity and explore underlying mechanisms by which B4G2 induces apoptosis. Results: Among these cell lines, HepG2 showed the highest sensitivity to B4G2. HepG2 cells treated with B4G2 showed a depolarized mitochondrial membrane potential, released cytochrome c, activated caspase-9 and caspase-3 and cleaved poly ADP-ribose polymerase (PARP). However, Z-VAD-FMK, a pan-caspase inhibitor, did not attenuate B4G2-induced apoptosis, implying that the induction of mitochondrial apoptosis by B4G2 may be independent of caspases. Moreover, pre-treatment with MgCl2, a blocker of Ca2+-dependent permeability transition (PT) pores, attenuated the depolarization of the mitochondrial potential and decreased the population of apoptotic cells, indicating that B4G2-induced apoptosis was partly dependent on the opening of the Ca2+-dependent PT pores. B4G2 also increased the levels of intracellular calcium and reactive oxygen species (ROS). Furthermore, an ROS scavenger, N-acetyl-cysteine (NAC), markedly decreased the accumulation of intracellular calcium and apoptosis. Conclusion: This is the first demonstration that B4G2 inhibits the growth of HCC cells and induces mitochondrial apoptosis in hepatocellular carcinoma cells by the ROS-mediated opening of Ca2+-dependent permeability transition pores.

scholarly journals Design, Synthesis, and Biological Evaluation of Novel Nitrogen Heterocycle-Containing Ursolic Acid Analogs as Antitumor Agents

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 877 ◽  
Author(s):  
Wenzhi Wang ◽  
Lei Lei ◽  
Zhi Liu ◽  
Hongbo Wang ◽  
Qingguo Meng
Keyword(s):  
Cell Lines ◽  
Ursolic Acid ◽  
Antitumor Agents ◽  
Biological Evaluation ◽  
Nitrogen Heterocycle ◽  
Mitochondrial Potential ◽  
Design Synthesis ◽  
Induced Apoptosis ◽  
Mkn45 Cell

Nineteen ursolic acid analogues were designed, synthesized, and evaluated for their antiproliferative activity against the Hela and MKN45 cell lines. Some compounds containing a piperazine moiety displayed moderate to high levels of antitumor activities against the tested cancer cell lines. The most potent compound shares the IC50 value of 2.1 µM and 2.6 µM for the Hela and MKN45 cell lines, respectively. Further mechanism studies and in vivo antitumor studies have shown that it decreased the apoptosis regulator (BCL2/BAX) ratio, disrupted mitochondrial potential and induced apoptosis, and suppressed the growth of Hela xenografts in nude mice.

miR-221/222 suppression protects against endoplasmic reticulum stress-induced apoptosis via p27Kip1- and MEK/ERK-mediated cell cycle regulation

2010 ◽  
Vol 391 (7) ◽  
Author(s):  
Rongyang Dai ◽  
Juan Li ◽  
Youping Liu ◽  
Dongmei Yan ◽  
Shaokun Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Cycle Regulation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Apoptosis Regulation ◽  
Cycle Regulation ◽  
Hcc Cells

Abstract Cancer cells are relatively resistant to endoplasmic reticulum (ER) stress-induced apoptosis. However, the underlying mechanisms remain largely unclear. We observed that the microRNAs miR-221/222 are associated with apoptosis regulation under ER stress in human hepatocellular carcinoma (HCC) cells. Induction of ER stress does not trigger significant apoptosis but obviously causes downregulation of miR-221/222 in HCC cells. In these cells, ER stress-induced apoptosis is enhanced by miR-221/222 mimics and attenuated by miR-221/222 inhibitors. miR-221/222 promoted-apoptosis under ER stress is associated with p27Kip1- and MEK/ERK-mediated cell cycle regulation. Our results suggest that suppression of miR-221/222 plays a crucial role in the protection against apoptosis induced by ER stress in HCC cells.

scholarly journals Restoration of Epigenetically Silenced Sulfatase 1 Expression by 5-Aza-2′-Deoxycytidine Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy-Induced Apoptosis

2015 ◽  
Vol 3 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Abdirashid Shire ◽  
Gwen Lomberk ◽  
Jin-Ping Lai ◽  
Hongzhi Zou ◽  
Norihiko Tsuchiya ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Methylation ◽  
Protein Expression ◽  
Mrna Expression ◽  
Cell Lines ◽  
Gene Copy ◽  
Drug Induced ◽  
Sulfatase Activity ◽  
Induced Apoptosis ◽  
Hcc Cells

Background: Hepatocellular carcinoma (HCC) is the second most frequent cause of cancer death worldwide. Sulfatase 1 (SULF1) functions as a tumor suppressor in HCC cell lines in vitro but also has an oncogenic effect in some HCCs in vivo. Aim: The purpose of this study was to examine the mechanisms regulating SULF1 and its function in HCC. Methods: First, SULF1 mRNA and protein expression were examined. Second, we examined SULF1 gene copy numbers in HCC cells. Third, we assessed whether DNA methylation or methylation and/or acetylation of histone marks on the promoter regulate SULF1 expression. Finally, we examined the effect of 5-aza-2′-deoxycytidine (5-Aza-dC) on sulfatase activity and drug-induced apoptosis. Results: SULF1 mRNA was downregulated in nine of eleven HCC cell lines, but only in six of ten primary tumors. SULF1 mRNA correlated with protein expression. Gene copy number assessment by fluorescence in situ hybridization showed intact SULF1 alleles in low-SULF1-expressing cell lines. CpG island methylation in the SULF1 promoter and two downstream CpG islands did not show an inverse correlation between DNA methylation and SULF1 expression. However, chromatin immunoprecipitation showed that the SULF1 promoter acquires a silenced chromatin state in low-SULF1-expressing cells through an increase in di/trimethyl-K9H3 and trimethyl-K27H3 and a concomitant loss of activating acetyl K9, K14H3 marks. 5-Aza-dC restored SULF1 mRNA expression in SULF1-negative cell lines, with an associated increase in sulfatase activity and sensitization of HCC cells to cisplatin-induced apoptosis. Conclusion: SULF1 gene silencing in HCC occurs through histone modifications on the SULF1 promoter. Restoration of SULF1 mRNA expression by 5-Aza-dC sensitized HCC cells to drug-induced apoptosis.

scholarly journals Baicalein Induces Apoptosis and Autophagy via Endoplasmic Reticulum Stress in Hepatocellular Carcinoma Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Zhongxia Wang ◽  
Chunping Jiang ◽  
Weibo Chen ◽  
Guang Zhang ◽  
Dongjun Luo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Intracellular Calcium ◽  
Water Soluble ◽  
Small Interfering Rnas ◽  
Therapeutic Drugs ◽  
Induced Apoptosis ◽  
Hcc Cells

Background. Hepatocellular carcinoma (HCC) remains a disastrous disease and the treatment for HCC is rather limited. Separation and identification of active compounds from traditionally used herbs in HCC treatment may shed light on novel therapeutic drugs for HCC.Methods. Cell viability and colony forming assay were conducted to determine anti-HCC activity. Morphology of cells and activity of caspases were analyzed. Antiapoptotic Bcl-2 family proteins and JNK were also examined. Levels of unfolded protein response (UPR) markers were determined and intracellular calcium was assayed. Small interfering RNAs (siRNAs) were used to investigate the role of UPR and autophagy in baicalein-induced cell death.Results. Among four studied flavonoids, only baicalein exhibited satisfactory inhibition of viability and colony formation of HCC cells within water-soluble concentration. Baicalein induced apoptosis via endoplasmic reticulum (ER) stress, possibly by downregulating prosurvival Bcl-2 family, increasing intracellular calcium, and activating JNK. CHOP was the executor of cell death during baicalein-induced ER stress while eIF2αand IRE1αplayed protective roles. Protective autophagy was also triggered by baicalein in HCC cells.Conclusion. Baicalein exhibits prominent anti-HCC activity. This flavonoid induces apoptosis and protective autophagy via ER stress. Combination of baicalein and autophagy inhibitors may represent a promising therapy against HCC.

scholarly journals Protection from inactivation of the adenine nucleotide translocator during hypoglycaemia-induced apoptosis by mitochondrial phospholipid hydroperoxide glutathione peroxidase

2003 ◽  
Vol 371 (3) ◽  
pp. 799-809 ◽  
Author(s):  
Hirotaka IMAI ◽  
Tomoko KOUMURA ◽  
Ryo NAKAJIMA ◽  
Kazuhiro NOMURA ◽  
Yasuhito NAKAGAWA
Keyword(s):  
Glutathione Peroxidase ◽  
Adenine Nucleotide ◽  
Control Level ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocator ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Phospholipid Hydroperoxide ◽  
Cyt C ◽  
Permeability Transition Pores ◽  
Induced Apoptosis

We demonstrated that mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) first suppressed the dissociation of cytochrome c (cyt c) from cardiolipin (CL) in mitochondrial inner membranes and then apoptosis caused by the hypoglycaemia by the prevention of peroxidation of CL [Nomura, Imai, Koumura, Arai and Nakagawa (1999) J. Biol. Chem. 274, 29294–29302; Nomura, Imai, Koumura, Kobayashi and Nakagawa (2000) Biochem. J. 351, 183–193]. The present study shows the involvement of peroxidation of CL in the inactivation of adenine nucleotide translocator (ANT) and the opening of permeability transition pores by using the system of ANT-reconstituted liposome and isolated mitochondria. ANT activity appeared in dioleoyl phosphatidylcholine proteoliposome containing 10% (mol/mol) CL or phosphatidylglycerol (PG), but not other classes of phospholipids. ANT activity was competitively inhibited by the addition of cardiolipin hydroperoxide (CLOOH) in reconstituted liposomes containing CL. However, phosphatidylcholine hydroperoxide failed to inactivate the activity of ANT. The activity of ANT in reconstituted liposomes, including CLOOH, recovered when CLOOH in reconstituted liposome was reduced to hydroxycardiolipin by incubation with PHGPx. The activity of ANT was determined in rat basophil leukaemia RBL2H3 cells after their exposure to 2-deoxyglucose. ANT activity decreased to 50% of the control level by 4 h in response to apoptosis. In parallel, cyt c and apoptosis-inducing factor (AIF) were released from mitochondria. Suppression of the accumulation of CLOOH by overexpression of PHGPx in mitochondria effectively prevented the inactivation of ANT, the opening of permeability transition pores and the release of cyt c and AIF from mitochondria in hypoglycaemia-induced apoptotic cells. These findings suggest that mitochondrial PHGPx might be involved in the modulation of the activity of ANT and the opening of pores for the release of cyt c via the modulation of levels of CLOOH in the mitochondria.

Complete Loss or Severely Compromised Expression of the Pro-Apoptotic Protein Bax Leads to Resistance to Curcumin-Induced Apoptosis in Burkitt’s Lymphoma Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1928-1928 ◽  
Author(s):  
Azhar R. Hussain ◽  
Maha Al-Rasheed ◽  
Pulicat S. Manogaran ◽  
Khawla S. Al-Kuraya ◽  
Shahab Uddin
Keyword(s):  
Cell Lines ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Curcumin Treatment ◽  
Lymphoma Cells ◽  
Mitochondrial Potential ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract This report compares in detail, the role of curcumin treatment in a panel of Burkitt’s lymphoma (BL) cell lines that are either expressing full length Bax with a group of cell lines that are either completely deficient or have decreased expression of Bax. Multiple apoptotic stimuli induce conformational changes in Bax, a pro-apoptotic protein from the Bcl-2 family and its deficiency is a frequent cause of chemo-resistance in a variety of malignancies including Burkitt’s lymphoma. We extent our previous studies on Burkitt’s lymphoma to determine the role of curcumin treatment on BLs. Curcumin (diferuloymethane) is a naturally occurring yellow pigment isolated from the rhizomes of the plant curcuma longa. The medicinal value of curcumin has been well recognized with its anti-oxidant, anti-inflammatory and anti-tumor activities. Curcumin is also known to induce apoptosis in a variety of cancer cells including multiple myeloma and primary effusion lymphomas. To understand the role of Bax in curcumin-induced apoptosis, we used two groups of Burkitt’s lymphoma cell lines, one that expressed the Bax protein (AS283A, KK124 and Pa682PB) and the other group either did not or had decreased expression of Bax (BML895 CA46, and LW878). Cell viability decreased in a dose-dependent manner in AS283A, PA682PB and KK124 with curcumin treatment ranging between 0–40mM whereas only minimal changes in viability was observed in BML895, CA46 and LW878 after treatment. Curcumin induced a dose-dependent apoptosis in the Bax expressing group of cell lines while the cell lines that were either completely deficient or had decreased expression of Bax did not respond to curcumin treatment and remained refractory. In AS283A, KK124, and PA682PB, curcumin induced apoptosis through truncation of BID, loss of mitochondrial potential as determined by JC1 staining with subsequent activation of caspase3 followed by cleavage of PARP. However, in the curcumin resistant cell lines, there was no change in the mitochondrial potential after curcumin treatment and therefore apoptosis did not occur. In addition, zVAD-fmk, a universal inhibitor of caspases prevented caspase3 cleavage as well as cell death in the sensitive cell lines after curcumin treatment suggesting that curcumin-induced apoptosis is caspase dependent. Our findings suggest that Bax integrity is necessary for curcumin to induce apoptosis in Burkitt’s lymphoma cells. These results provide the molecular basis and preliminary data for new treatment strategies that may incorporate curcumin in regimens for Burkitt’s lymphoma treatment.

Sign in / Sign up

Export Citation Format

Share Document