Conventional calpains and programmed cell death.

The evidence on the crucial role of a family of calcium-dependent cysteine proteases called calpains in programmed cell death is rich and still growing. However, understanding of the mechanisms of their functions in apoptosis is not full yet. Calpains have been implicated in both physiological and pathological cell death control, especially in various malignancies, but also in the immune system development and function. There is also growing evidence on calpain involvement in apoptosis execution in certain pathological conditions of the central nervous system, in cardiovascular diseases, etc. Understanding of the clinical significance of calpain activation pathways, after intense studies of the influence of calpain activity on drug-induced apoptosis, seems especially important lately, as calpains have become noticed as potential therapeutic targets. To allow pharmacological targeting of these enzymes, thorough knowledge of their patterns of activation and further interactions with already known apoptotic pathways is necessary. A comprehensive summary of both well established and recently obtained information in the field is an important step that may lead to future advances in the use of calpain-targeted agents in the clinic.

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Distinct Apoptotic Responses Imparted by c-myc and max

Blood ◽

10.1182/blood.v92.3.1003 ◽

1998 ◽

Vol 92 (3) ◽

pp. 1003-1010 ◽

Cited By ~ 13

Author(s):

Chadd E. Nesbit ◽

Saijun Fan ◽

Hong Zhang ◽

Edward V. Prochownik

Keyword(s):

Cell Death ◽

Cell Lines ◽

Ectopic Expression ◽

Drug Induced ◽

Enhanced Sensitivity ◽

Contrast Enhanced ◽

Apoptotic Pathways ◽

American Society ◽

Induced Apoptosis ◽

Cytokine Deprivation

Abstract The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc– and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc–overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc–overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways. © 1998 by The American Society of Hematology.

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Distinct Apoptotic Responses Imparted by c-myc and max

Blood ◽

10.1182/blood.v92.3.1003.415a19_1003_1010 ◽

1998 ◽

Vol 92 (3) ◽

pp. 1003-1010 ◽

Cited By ~ 1

Author(s):

Chadd E. Nesbit ◽

Saijun Fan ◽

Hong Zhang ◽

Edward V. Prochownik

Keyword(s):

Cell Death ◽

Cell Lines ◽

Ectopic Expression ◽

Drug Induced ◽

Enhanced Sensitivity ◽

Contrast Enhanced ◽

Apoptotic Pathways ◽

American Society ◽

Induced Apoptosis ◽

Cytokine Deprivation

The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc– and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc–overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc–overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways. © 1998 by The American Society of Hematology.

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Investigating Programmed Cell Death and Tumor Invasion in a Three-Dimensional (3D) Microfluidic Model of Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms21093162 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3162

Author(s):

Ehsan Samiei ◽

Amir Seyfoori ◽

Brian Toyota ◽

Saeid Ghavami ◽

Mohsen Akbari

Keyword(s):

Cell Death ◽

Survival Rate ◽

Programmed Cell Death ◽

Tumor Invasion ◽

3D Model ◽

Apoptotic Cell ◽

Simultaneous Detection ◽

Three Dimensional ◽

Drug Induced ◽

Induced Apoptosis

Glioblastoma multiforme (GBM) is a rapidly progressive and deadly form of brain tumor with a median survival rate of ~15 months. GBMs are hard to treat and significantly affect the patient’s physical and cognitive abilities and quality of life. Temozolomide (TMZ)—an alkylating agent that causes DNA damage—is the only chemotherapy choice for the treatment of GBM. However, TMZ also induces autophagy and causes tumor cell resistance and thus fails to improve the survival rate among patients. Here, we studied the drug-induced programmed cell death and invasion inhibition capacity of TMZ and a mevalonate cascade inhibitor, simvastatin (Simva), in a three-dimensional (3D) microfluidic model of GBM. We elucidate the role of autophagy in apoptotic cell death by comparing apoptosis in autophagy knockdown cells (Atg7 KD) against their scrambled counterparts. Our results show that the cells were significantly less sensitive to drugs in the 3D model as compared to monolayer culture systems. An immunofluorescence analysis confirmed that apoptosis is the mechanism of cell death in TMZ- and Simva-treated glioma cells. However, the induction of apoptosis in the 3D model is significantly lower than in monolayer cultures. We have also shown that autophagy inhibition (Atg7 KD) did not change TMZ and Simva-induced apoptosis in the 3D microfluidic model. Overall, for the first time in this study we have established the simultaneous detection of drug induced apoptosis and autophagy in a 3D microfluidic model of GBM. Our study presents a potential ex vivo platform for developing novel therapeutic strategies tailored toward disrupting key molecular pathways involved in programmed cell death and tumor invasion in glioblastoma.

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Antibody against single-stranded DNA detects both programmed cell death and drug-induced apoptosis

Histochemistry ◽

10.1007/bf00315834 ◽

1994 ◽

Vol 101 (1) ◽

pp. 73-78 ◽

Cited By ~ 94

Author(s):

I. Naruse ◽

H. Keino ◽

Y. Kawarada

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Drug Induced ◽

Single Stranded Dna ◽

Induced Apoptosis

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Beyond apoptosis: nonapoptotic cell death in physiology and disease

Biochemistry and Cell Biology ◽

10.1139/o05-065 ◽

2005 ◽

Vol 83 (5) ◽

pp. 579-588 ◽

Cited By ~ 45

Author(s):

Claudio A Hetz ◽

Vicente Torres ◽

Andrew F.G Quest

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Death Receptor ◽

Receptor Signaling ◽

Family Analysis ◽

Caspase Family ◽

Death Receptor Signaling ◽

Apoptotic Pathways ◽

Nonapoptotic Cell Death ◽

High Degree

Apoptosis is a morphologically defined form of programmed cell death (PCD) that is mediated by the activation of members of the caspase family. Analysis of death-receptor signaling in lymphocytes has revealed that caspase-dependent signaling pathways are also linked to cell death by nonapoptotic mechanisms, indicating that apoptosis is not the only form of PCD. Under physiological and pathological conditions, cells demonstrate a high degree of flexibility in cell-death responses, as is reflected in the existence of a variety of mechanisms, including necrosis-like PCD, autophagy (or type II PCD), and accidental necrosis. In this review, we discuss recent data suggesting that canonical apoptotic pathways, including death-receptor signaling, control caspase-dependent and -independent cell-death pathways.Key words: apoptosis, necrosis, nonapoptotic programmed cell death, death receptors, ceramides.

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Programmed Cell Death and Apoptosis in Lymphocyte Development and Function

CHEST Journal ◽

10.1378/chest.103.2_supplement.99s ◽

1993 ◽

Vol 103 (2) ◽

pp. 99S-101S ◽

Cited By ~ 18

Author(s):

J.John Cohen

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Lymphocyte Development ◽

And Function

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Neuronal apoptosis: signal and cell diversity

Colombia Medica ◽

10.25100/cm.v40i1.634 ◽

1969 ◽

Vol 40 (1) ◽

pp. 124-133

Author(s):

Lina Vanessa Becerra ◽

Hernán José Pimienta

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Neuronal Response ◽

Neuronal Cell ◽

Cell Types ◽

Point Of View ◽

Trophic Factors ◽

Cell Diversity ◽

Apoptotic Pathways ◽

The Brain

Programmed cell death occurs as a physiological process during development. In the brain and spinal cord this event determines the number and location of the different cell types. In adulthood, programmed cell death or apoptosis is more restricted but it may play a major role in different acute and chronic pathological entities. However, in contrast to other tissues where apoptosis has been widely documented from a morphological point of view, in the central nervous system complete anatomical evidence of apoptosis is scanty. In spite of this there is consensus about the activation of different signal systems associated to programmed cell death. In the present article we attempt to summarize the main apoptotic pathways so far identified in nervous tissue. Considering that apoptotic pathways are multiple, the neuronal cell types are highly diverse and specialized and that neuronal response to injury and survival depends upon tissue context, (i.e., preservation of connectivity, glial integrity and cell matrix, blood supply and trophic factors availability) what is relevant for the apoptotic process in a sector of the brain may not be important in another.

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EXPERIMENTAL MODELING OF APOPTOSIS UNDER CONDITIONS OF STABLE STRONTIUM EXPOSURE

Medical Immunology (Russia) ◽

10.15789/1563-0625-2019-1-137-140 ◽

2019 ◽

Vol 21 (1) ◽

pp. 137-140

Author(s):

O. V. Dolgikh ◽

N. V. Zaitseva ◽

D. G. Dianova ◽

A. V. Krivtsov ◽

K. D. Starkova ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Death ◽

Programmed Cell Death ◽

Annexin V ◽

Fold Increase ◽

Apoptosis Markers ◽

Stable Strontium ◽

Cell Death Mechanisms ◽

Apoptotic Pathways ◽

And Control

Apoptosis is defined as a highly regulated form of programmed cell death with typical morphological and biochemical features. A variety of factors, including heavy metals, may influence the intensity of programmed cell death. The aim of the work was to simulate apoptosis in an in vitrosystem under the conditions of stable strontium exposure. The children’s population consuming drinking water with high strontium (Sr2+) content (n = 49) was observed. The level of lymphocyte apoptosis was determined with flow cytometry technique, by means of labeled annexin V-FITC conjugate (AnnV-FITC) and propidium iodide (PI) staining. AnnV-FITC+PI- cells were regarded as early apoptotic forms, whereas late apoptotic and/or necrotic cells were AnnV-FITC+PI+. The isolated leukocytes were incubated with Sr2+ at a concentration of 7.0 mg/l, the maximal permitted concentration (MPC) for water of aqueous objects, for 4 hours at 37 ºC. Expression of CD95 and p53 apoptosis markers was performed by flow cytometry using labeled monoclonal antibodies.In vitroexposure to strontium was associated with significantly decreased expression of apoptosisregulating factors, i.e., membrane marker CD95 and intracellular transcription protein p53, 1.56- and 1.68-fold, respectively. Meanwhile, we revealed a significantly (4.68-fold) decreased amounts of AnnV-FITC+PI--cells, as well as a statistically significant (1.35-fold) increase of the AnnV-FITC+PI+-cells. Moreover, the amounts of AnnV-FITC+ PI--lymphocytes in all samples were below the physiological ranges and control values. The number of samples with higher contents of AnnV-FITC+PI+-lymphocyte exceeding the established standards and control values, was 30.8%. Thus, it has been experimentally proven that strontium, at a concentration corresponding to MPC for water objects may significantly inhibit cell death along apoptotic pathways, with switching to necrotic cell death mechanisms, according to phosphatidylserine contents, as detected by annexin V binding test. The data have revealed an ability of strontium to have a significant effect upon the parameters of regulation and maintenance of cellular homeostasis, by influencing the apoptosis intensity, due to shifting a balance towards necrosis and reducing expression of apoptosis-regulating factors. The results of this study may be used in order to identify some marker indexes of immune disorders potentially induced by external influence of strontium upon human health under specific environmental factors.

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