scholarly journals Mitochondrial membrane permeabilization and cell death during myocardial infarction: roles of calcium and reactive oxygen species

2012 ◽  
Vol 8 (6) ◽  
pp. 863-884 ◽  
Author(s):  
Keith A Webster
Keyword(s):  
Myocardial Infarction ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen ◽  
Membrane Permeabilization ◽  
Oxygen Species ◽  
Mitochondrial Membrane Permeabilization

scholarly journals Lysosome Membrane Permeabilization Causes Cell Death in Primary Chronic Lymphocytic Leukemia Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 930-930 ◽  
Author(s):  
Rebecca Dielschneider ◽  
Hannah Eisenstat ◽  
James B. Johnston ◽  
Spencer B Gibson
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Reactive Oxygen ◽  
Membrane Permeabilization ◽  
Lymphocytic Leukemia ◽  
Oxygen Species ◽  
Lysosome Membrane

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in North America. Despite many therapeutic advances over the past decade, drug resistance and disease recurrence are common. Novel therapeutic approaches are therefore required to treat CLL. One novel target identified in a variety of cancers, including acute myeloid leukemia, is the lysosome. In transformed cancerous cells, lysosomes were found to be sensitive to permeabilization by lysotropic agents in a process called lysosome membrane permeabilization. Permeabilization of lysosomes releases their acidic and proteolytic contents into the cytoplasm causing lysosome-mediated cell death. The therapeutic strategy of targeting lysosomes has yet to be determined in CLL. Methods: Primary CLL cells were purified from patient peripheral blood using negative selection and separated on a ficoll gradient. Three different lysosome-targeting drugs used in the clinic for other purposes were investigated: a quinolone, a fluoroquinolone antibiotic, and a cationic drug (CAD). To determine the mechanism of action, various dyes were used to stain lysosomes, mitochondria, and reactive oxygen species. Fluorescence was visualized under the confocal microscope and quantified using flow cytometry. To determine the role of reactive oxygen species (ROS) the antioxidants α-tocopherol, lycopene, N-acetyl cysteine, and glutathione were added to cells. To determine the role of proteases the inhibitors zVADfmk, Ca-074-Me, Chymostatin, and E64 were added to cells. Results: All the lysotropic agents except the antibiotic effectively killed CLL cells isolated from patients. The CAD had the greatest activity and was significantly more cytotoxic to the CLL cells as compared to T cells from the same patients and peripheral blood mononuclear cells from non-CLL donors. Treatment was equally effective in p53-proficient and p53-deficient CLL cells, demonstrating that the most aggressive and drug-resistant CLL cells were sensitive to this CAD. Mechanistic studies revealed that lysosome membrane permeabilization occurred within minutes and led to an increase in ROS and loss of mitochondrial membrane potential. The permeabilization of lysosomes was further confirmed by the translocation of transcription factor EB (TFEB) into the nucleus indicating promotion of lysosomal biogenesis. Lipid ROS were necessary to induce cell death, as only lipophilic antioxidants prevented cell death. Lipophilic antioxidants did not prevent lysosomal permeabilization, but did prevent downstream mitochondrial dysfunction. Inhibitors of caspases and lysosomal cathepsins failed to prevent cell death in CLL cells. Conclusions: Results show that the lysosome-targeting quinolone and CAD effectively permeabilize lysosomes and induce lysosome-mediated cell death in primary human CLL cells. This unique mechanism of cell death in CLL is dependent on the generation of lipid ROS, but not on the action of caspases or cathepsins. Overall, targeting lysosomes may be an effective strategy to selectively kill CLL cells regardless of p53 expression. Future studies are focused on the lysosomal differences in B cells and CLL cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

Tumor Biology ◽  
2017 ◽  
Vol 39 (2) ◽  
pp. 101042831769431 ◽  
Author(s):  
Satabdi Datta ◽  
Diptiman Choudhury ◽  
Amlan Das ◽  
Dipanwita Das Mukherjee ◽  
Nabanita Das ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Resistance Development

Paclitaxel (Tx) is one of the first-line chemotherapeutic drugs used against lung cancer, but acquired resistance to this drug is a major challenge against successful chemotherapy. In this work, we have focused on the chronological changes of various cellular parameters and associated effect on Tx (10 nM) resistance development in A549 cell line. It was observed, at initial stage, the cell death percentage due to drug treatment had increased up to 20 days, and thereafter, it started declining and became completely resistant by 40 days. Expressions of βIII tubulin and drug efflux pumps also increased over the period of resistance development. Changes in cellular autophagy and reactive oxygen species generation showed a biphasic pattern and increased gradually over the course of upto 20 days, thereafter declined gradually; however, their levels remained higher than untreated cells when resistance was acquired. Increase in extracellular acidification rates and oxygen consumption rates was found to be directly correlated with acquisition of resistance. The depolarisation of mitochondrial membrane potential was also biphasic; first, it increased with increase of cell death up to 20 days, thereafter, it gradually decreased to normal level along with resistance development. Increase in activity of catalase, glutathione peroxidase and glutathione content over these periods may attribute in bringing down the reactive oxygen species levels and normalisation of mitochondrial membrane potential in spite of comparatively higher reactive oxygen species production by the Tx-resistant cells.

Reserpine Induces Apoptosis and Cell Cycle Arrest in Hormone Independent Prostate Cancer Cells through Mitochondrial Membrane Potential Failure

2019 ◽  
Vol 18 (9) ◽  
pp. 1313-1322 ◽  
Author(s):  
Manjula Devi Ramamoorthy ◽  
Ashok Kumar ◽  
Mahesh Ayyavu ◽  
Kannan Narayanan Dhiraviam
Keyword(s):  
Prostate Cancer ◽  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Membrane Potential ◽  
Cancer Cells ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Prostate Cancer Cells

Background: Reserpine, an indole alkaloid commonly used for hypertension, is found in the roots of Rauwolfia serpentina. Although the root extract has been used for the treatment of cancer, the molecular mechanism of its anti-cancer activity on hormonal independent prostate cancer remains elusive. Methods: we evaluated the cytotoxicity of reserpine and other indole alkaloids, yohimbine and ajmaline on Prostate Cancer cells (PC3) using MTT assay. We investigated the mechanism of apoptosis using a combination of techniques including acridine orange/ethidium bromide staining, high content imaging of Annexin V-FITC staining, flow cytometric quantification of the mitochondrial membrane potential and Reactive Oxygen Species (ROS) and cell cycle analysis. Results: Our results indicate that reserpine inhibits DNA synthesis by arresting the cells at the G2 phase and showed all standard sequential features of apoptosis including, destabilization of mitochondrial membrane potential, reduced production of reactive oxygen species and DNA ladder formation. Our in silico analysis further confirmed that indeed reserpine docks to the catalytic cleft of anti-apoptotic proteins substantiating our results. Conclusion: Collectively, our findings suggest that reserpine can be a novel therapeutic agent for the treatment of androgen-independent prostate cancer.

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