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High Concentrations Of Anaerobic Atp Implicated In Aborted Apoptosis From Cll
Author: Aurelian Udristioiu
Publisher: Emergency County Hospital TARGU-JIU
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Description:

 

Introduce

    Chronic lymphocytic leukemia, (also known as "chronic lymphoid leukemia" or CLL), is a type

of leukemia or cancer of the white blood cells, lymphocytes. The cells accumulate mainly in the

bone marrow and blood.  Morphologically, these cells resemble mature lymphocytes in the

peripheral blood. In the majority of patients with chronic CLL the cells are clonal B cells arrested in

the B-cell differentiation pathway between pre-B cells and mature B cells. Only 2-5% of patients

with chronic CLL exhibit a T-cell phenotype. In CLL the DNA of a B cell is mutated so that it can't

fight infection, but it grows out of control and crowds out the healthy blood cells that can fight

infection. Theoretical studies have suggested that elevated concentration of adenosine-triphosphate

(ATP) in malignant B cells lymphocytes from CLL impair P53 gene to induce apoptosis of cells.

Apoptosis is regulated by a cascade of proteins called caspases that are present in all cells forms as

pro-form. After cleavage, caspases become active and initiate pathways leading to apoptosis. The

pro-apoptotic proteins Bax, Bad, Bak and Bid induce programmed cell death. Death resistance of

hypoxia takes place on at least two levels, within mitochondria and the cytosol. Accumulation of

Bax in the mitochondria causes the release of cytochrome C in cytosol that is strongly reduced

under hypoxic environment conditions [Figure 1]. Apoptosis, performed within the extrinsic

pathway, is initiated by death ligands, such as Fas ligand or tumor necrosis factor (TNF), which

ultimately leads to the activation of caspases 8 and 3 and the activation of apoptosis protein

activating factor (APAF). All hematopoietic cells, especially lymphoid cells, express Bcl-2, mainly

in the nucleus and endoplasm reticulum. The oncogene Bcl-2 may be a general suppressor of genes

that directly regulate apoptosis.

Scope

 

       The main objective of the study was to measure the intracellular ATP concentrations in B

 

lymphocytes from patients with CLL, and compare to  ATP  concentrations in B and T cells from

 

healthy patients and patients with other malignant diseases or non-malignant diseases.

 

Materials and methods

   

    The measurement of ATP was made by standard principle of bioluminescence on automatic

 

analyzer LKB, using ATP monitoring reagent, ATP Standard, (106 Mol ATP/ ml), buffer solution

 

Tris-EDTA, TCA-EDTA lyse. All results were statistically analyzed by Excel program. T

 

lymphocytes were obtained from the peripheral blood of healthy individual and from hospitalized

 

patients with selected diseases from the departments of Internal Medicine and Oncology. Patient

 

cohort was a total of 75 patients (50 males and 25 females) consisting of the following groups were

 

examined: 25 patients (mean ages 55 ± 0.5)), with allergic  diseases  (allergic rhinitis, allergic

 

dermatitis , chronic allergic asthma), 25 patients( mean  ages 58 ± 1.8 ) with nonhematopoietc

 

malignant diseases ( lung cancer, bone metastasis) and 25 patients with confirmed hematopoietic

 

malignant disorders, in  diagnosis of CLL.

 

    In addition, 120 blood samples from apparently healthy donors (mean ages 40.02 ±12.01) were

 

also examined. The May Grunwald-Giemsa method was used to determine the microscopic

 

appearance of peripheral blood  lymphocytes from  patients with incipient CLL disease, who had not

 

had any treatment or hematopoietic stem cell transplantation (HSCT).Morphologically, the cells

 

resembled normal mature clonal B cells arrested in the B- cell differentiation pathway intermediate

 

between pre-B cells and mature B cells lymphocytes although slightly larger, and more fragile when

 

smeared onto a glass slide(smudge cells)Lymphocytes were separated from peripheral blood  by

 

centrifugation in a Ficoll gradient for 20 minutes at 2000 rcf/ minute. Lysis of lymphocytes with 

 

TCA-EDTA was performed after cell counts were adjusted to 1 x 106 lymphocytes /ml of

 

plasma. An initial panel of monoclonal antibodies was used to immune-phenotype T cells and their

 

subgroups and B cells and their subgroups.

 

    Immune-cytochemical detection of antigen was made using the ABC-AP, APAAP method.

 

Activated B lymphocytes were defined as CD19 + cells, CD20, CD21, and CD23 and or CD138

 

surface marker. Activated T cells were identified with CD7, CD5, CD3, CD2, CD4, CD8 and

 

CD45RO. The phenotype suggestive of B-CLL or monoclonal B cell lymphocytes was

 

approximately equal numbers of CD5+ and CD19+ lymphocytes.  For monitoring diagnosis and

 

prognosis of CLL, the samples were sent to the National Institute of Reference Oncology, Fundeni.

 

Expected values to cytogenetic results [7] will the deletion13q chromosome that can occurs in

 

more than 50% of patients and trisomy 12, which can occurs in about 60 of patients.

 

Individual13q14 abnormalities have a relatively benign disease that usually manifests as stable or

 

slowly progressive isolated lymphocytosis. Deletion in the short arm of chromosome 17 is associated

 

with rapid progression, short remission, and decreased overall survival in chronic CLL. The 17p13

 

deletions are associated with loss of function of the tumor suppressor gene p53 and deletions of

 

bands 11q22-q23, associated with extensive lymph node, involvement aggressive disease and shorter

 

survival.

 

  In the differential diagnosis of CLL we included:

 

-Hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of

 

multiple heavy-chain classes and is typically negative for CD5 and CD21.

 

-CLL should also be distinguished from pro-lymphocytic leukemia, in which more than 65% of the

 

cells are morphologically less mature pro-lymphocytes.

 

- Proymphocytic leukemia has a typical phenotype that is positive for CD19, CD20, and surface

 

membrane immunoglobulin but one half will be negative for CD5.

 

- Large granular lymphocytic leukemia has a natural killer (NK) cell phenotype (CD2, CD16, CD56)

or a T-cell immune-type (CD2, CD3, CD8).

-Pattern of positively for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell

lymphoma and these cells generally do not express CD23.

Results:

 

In the healthy male and female subjects, the mean concentration of ATP in 1 x 106 lymphocytes /ml

 

of normal peripheral blood T lymphocytes had was 1.39 µM ATP and in B lymphocytes the

 

concentration was 0.35 µM ATP/ml [SD = 0.41, p= 0.030]. The mean concentration of ATP in 1 x

 

106 activated peripheral blood T lymphocytes from patients with allergic diseases was 3.12 µM

 

ATP/ml and in B Lymphocytes the mean concentration was 0.79 µM ATP/ml [SD= 0.56, p = 0.034].

 

From   patients with malignant diseases, the concentration of ATP in 1 x 106 activated peripheral

 

blood T lymphocytes/ml had a mean value of 3.06 µM ATP  and the mean concentration of ATP in

 

activated B lymphocytes/ml was 0.17 µM ATP [SD= 0.45, p = 0.05]. The mean concentration of

 

ATP in 1 x 106 activated peripheral blood malignant CLL B lymphocytes/ml was 4.33 µM ATP but

 

was only 0.09 µM ATP [SD= 1.5, p < 0.05]  in T lymphocytes from these patients. A strong

 

correlation was observed between the concentration of ATP of T lymphocytes from patients with 

 

malignant diseases and ATP concentration of B lymphocytes from samples of patients with CLL (r=

 

0.99) and a good correlation was observed between T lymphocytes (Th) from allergic diseases and T

 

lymphocytes (Ts) from malignant diseases (r = 0.94). The difference of energy between anaerobic

 

ATP in B lymphocytes from CLL and aerobic ATP in T lymphocytes from healthy subjects have

 

been calculated in value of 2.68 µM ATP and suggests the process of carcinogenesis. Table 1

 

Discussion

 

    Otto Warburg observed that many cancers lose their capacity for mitochondrial respiration,

 

limiting ATP production to anaerobic glycolytic pathways [1]. The phenomenon is particularly

 

prevalent in aggressive malignancies, most of which are also hypoxic. Hypoxia induces a stochastic

 

imbalance between the numbers of reduced mitochondrial species vs. available oxygen, resulting in

 

increased reactive oxygen species (ROS) whose toxicity can lead to apoptotic cell death. 

 

Mechanism involves inhibition of glycolytic ATP production via a Randle-like cycle while increased

 

uncoupling renders cancers unable to produce compensatory ATP from respiration-.generation in the

 

presence of intact tricarboxylic acid (TCA) enzyme. One mitochondrial adaptation to increased ROS

 

is over-expression of the uncoupling protein 2 (UCP2) that has been reported in multiple  human

 

cancer cell lines [2-3]. Increased UCP2 expression was also associated with reduced ATP production

 

in malignant oxyphilic mouse leukemia and human lymphoma cell lines [4].  Hypoxia reduces the

 

ability of cells to maintain their energy levels, because less ATP is obtained from glycolysis than

 

from oxidative phosphorylation. Cells adapt to hypoxia by activating the expression of mutant genes

 

in glycolysis. Severe hypoxia causes a high mutation rate, resulting in point mutations that may be

 

explained by reduced DNA mismatch repairing activity.  The most direct induction of apoptosis

 

caused by hypoxia is determined by the inhibition of the electron carrier chain from the inner

 

membrane of the mitochondria. The lack of oxygen inhibits the transport of protons and thereby

 

causes a decrease in membrane potential. Cell survival under conditions of mild hypoxia is mediated

 

by phosphoinositide-3 kinase (PIK3) using severe hypoxia or anoxia, and then cells initiate a

 

cascade of events that lead to apoptosis. After DNA damage, a very important regulator of

 

apoptosis is the p53 protein. This tumor suppressor gene has mutations in over 60% of human

 

tumors and acts as a suppressor of cell division. The growth-suppressive effects of p53 are

 

considered to be mediated through the transcriptional trans-activation activity of the protein. In

 

addition to the maturational state of the clonal tumor, the prognosis of patients with CLL is

 

dependent of genetic changes within the neoplastic cell population.

 

    The genetic changes can be identified by fluorescent probes to chromosomal using a technique

 

referred to as fluorescent in situ hybridization (FISH). Chromosomal evaluation using FISH can

 

identify certain chromosomal abnormalities of CLL that have prognostic significance. Deletion of

 

part of the short arm of chromosome 17 (del 17 q), with target the cell cycle regulating protein p53,  

 

is particularly deleterious. This abnormality is found in 10% of patients with CCL and has a pour

 

prognosis. Deletion of long arm of chromosome 13(del 13q) is the most common genetic

 

abnormality in CLL with roughly 50% of patients exhibiting  this effect. These patients have

 

the best prognosis and most will live many years without the need for therapy. Agents damaging

 

DNA may increase the expression of p53 and its trans-activation activity, suggesting that p53 acts to

 

protect cells against the accumulation of mutants and their subsequent conversion to a malignant

 

status [Figure 2]. Protein p53, in its normal form, acts in stopping the cell division whenever damage

 

to a cell’s DNA is detected, thus giving the cells the possibility of repairing DNA before the errors

 

would duplicate and be passed on  to the daughter cells. Antibodies to human p53 have been

 

detected in patients with cancer. These antibodies are highly specific for malignant diseases and are

 

rarely detected in healthy donors or patients having  benign diseases. This immune response is

 

correlated with the presence of a p53 gene mutation, leading to the accumulation of an ineffective

 

p53 protein in tumor cells[ 8] with either tridimensional structure [ Figure 3} from normal

 

configuration [Figure  4]. Over-expression of normal p53 protein can result either in G1 arrest,

 

mediated by p21 protein [ Figure 5] or in the induction of apoptosis [ 9 ]. Also hypoxia itself can

 

also prevent apoptosis by inducing the expression of the anti apoptotic protein IAP-2. A typical

 

response to the hypoxic environment, by hypoxia inducible factor 1, [ 6] for example, is expression

 

of insulin-independent GLUT [5] triggered by HIF 1α [6] insuring maximum glucose uptake for

 

glycolytic ATP generation.

 

Conclusions:

 

    Blocked apoptosis from malignant diseases may be due to high ATP concentration originating

 

from anaerobic metabolism. The difference of energy between anaerobic ATP in B lymphocytes

 

from CLL and aerobic ATP in activated T lymphocytes from normal status and non-malignant

 

diseases was 2.68 µM ATP, as an energetic transfer between T and B cells, initiates carcinogenesis

 

by suppression of anti oncogene proteins, specially p53 protein. Further studies are necessary to

 

detect to patients with high  concentrations of ATP the mutations, translocations or deletions of the

 

p53 gene that is located on chromosome 17, using FISH technology.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Statement of Funds

 

[1].Grant/Funding Support. -Not Applicable

 

[2] Financial disclosures. - Not Applicable

 

[[3]. Acknowledgement- The author expresses his appreciation to Professor Mitchell G. Scott, for editing the manuscript.

-Address correspondence:  Department of Pathology and Immunology, Box 8118, Washington University School of Medicine, St. Louis, MO 63110. Fax 314-362-1461; e-mail mscott@labmed.wustl.edu .

 

 

Acknowledgments

Author Contributions: All authors confirmed they have contributedto the intellectual content of this paper and have met the following3 requirements: (a) significant contributions to the conceptionand design, acquisition of data, or analysis and interpretationof data; (b) drafting or revising the article for intellectualcontent; and (c) final approval of the published article.

Authors’ Disclosures of Potential Conflicts of Interest:No authors declared any potential conflicts of interest.

Role of Sponsor: The funding organizations played no role inthe design of study, choice of enrolled patients, review andinterpretation of data, or preparation or approval of manuscript

 

 

Author,

Aurelian Udristioiu

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REFERENCES

 

1.Warburg O. On the origin of cancer cells. Science 1956; 123 (3191):309-314

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in the inner mitochondrial membrane during mitochondrial reactive oxygen stress

 

in macrophages. Biochim Biophys Acta 2008, 1777(2):118-129. PubMed Abstract |

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3. Horimoto M, Resnick MB, Konkin TA, Routhier J, Wands JR, Baffy G. Expression of

 

uncoupling protein-2 in human colon cancer. Clin Cancer Res 2004; 10 (18 Pt1):6203-

 

6207. PubMed Abstract | Publisher Full Text OpenURL

 

4. Randle PJ, England PJ, Denton RM. Control of the tricarboxylate cycle and it 

 

interactions with glycolysis during acetate utilization in rat heart. Biochem J 1970; 

 

117(4):677-695. PubMed Abstract | PubMed Central Full Text OpenURL

 

5. Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose

 

metabolism of cancers. J Nucl Med 2008; 49(Suppl 2):24S-42S. PubMed Abstract |

Publisher Full Text OpenURL

 

6. Denko NC: Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev

 

Cancer 2008; 8(9):705-13. PubMed Abstract | Publisher Full Text OpenURL

 

7. Bennett J M. Practical of Diagnosis of Hematologic Disorders. Lett. Molecular

 

Prognostic Factors in Non – Hodgkin Lymphoma, Chronic Lymphocytic Leukemia,

 

Chicago, ASCP Press 2006; p.615 – 671

 

8. Whibley C, Pharoah P, Hollstein M. P53 Polymorphism: Cancer Implications. Nat Rev

 

Cancer 2009; (2): 95-107

 

9. Udristoiu A. Bioenergetica celulara normala si maligna. Bucuresti, Targu Jiu, Editura

 

Academica  Brancusi 2002; p. 200-239

 

 

 

 

 

 

 

 

 

 

 

 

 

 ATP µM concentration in 106 cells/mL T and B Lymphocytes

 

Normal conc. ATP in  T

cells

Normal conc. ATP in  B cells

Conc. ATP in T cells, allergic diseases

Conc. ATP in B cells, allergic diseases

Conc. ATP in  T cells, malignant diseases

Conc. ATP B cells, malignant disease

Conc. ATP in B cells, CLL

 

Conc. ATP in  T cells, CLL

x¯= 1.39

x¯=0.35

 

x¯= 3.12

x¯= 0.79

x¯== 3.06

x¯= 0.17

x¯=4.33

x¯= 0.09

 

SD = 0.41

SD = 0.42

SD =0.56

SD =0.57

SD = 0.46

SD = 0.45

SD =1.5

SD =1.7

 

 

Table1. The concentrations of µM APT in malignant and chronic diseases contented in 106 lymphocytes / ml, from peripheral blood

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                                    

    Figure Captions List:

 

 

 

Figure 1.The Cascade of caspases undergoing apoptosis

 

Figure 2. Interrelation between the p53 protein and apoptotic factors

 

Figure 3.Three-dimensional structure of p53 protein in its tetrameric form

 

Figure 4.The structure of the core domain of the p53 protein

 

Figure 5.The action of p21 protein in damaged DNA

 

 

About the publisher:

- My Book written in Clinical Laboratory Medicine, “ Hematological and Metabolical Aspects from Laboratory Medicine” , confirm the aria of my interest in discovery of carcinogenesis mechanisms, especially in onco-haematology field, Leukemia.

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Also, my new e-Book: e-BOOK: Hematological and Metabolical Aspects of Laboratory Medicine (Hematological and Metabolical Aspects from Laboratory Medicine) ( Second Edition ) [Large Print] [Paperback].

Publisher: Aurelian Udristioiu, 2 edition (September 9, 2013) Full Color on White paper, 122 pages. ISBN-13: 978-1492186816 (CreateSpace-Assigned) ISBN-10: 1492186813, BISAC: Medical / Laboratory Medicine, USA. Sold by www.amazon.com   

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RECENT WORK OF RESEARCHES

 

1. Udristioiu A. The Assessment of Uncertainty in Measurement of Cholesterol; A Model of Calculation. Biophysical Journal; Volume 96, Issue 3, Supplement 1, February 2009; Page 504a.

2. Udristioiu A, Florescu Cristina, Popescu Manuela Andrei. “High Concentration of anaerobic ATP implicated in aborted apoptosis from CLL”. LabMedicine, American Journal of Clinical Pathology-ASCP, Manuscript 09-08-LM-S-SCI-0122R1, Published in 04-05/2010.

3. Aurelian Udristioiu. First Hematological Signal of Latent Anemia to Aging Population. Nature Publishing Group. Advance Search 0.1038 npre 2009.3285.1. Creative Common Attribution 3.0 License, accepted for the work online posted.

4. Udristioiu A, Cojocaru M, Florescu C. Screening Tests for Latent Anemia in Hospitalized Adults Over 65.   LabMedicine, American Journal of Clinical Pathology-ASCP, Manuscript  09-11-LM-S-SCI-0156.R1,  Published  in 07-05/2010.USA American Journal of Clinical Pathology p-ISSN: 0002-9173 ICV 38.53 LabMedicine ; Ascp Press) , Impact Factor ISI, IF = 2.853 , 18 Index Copernicus Journals Master List 2006.

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1 University of Medicine and Pharmacy “Carol Davila, Faculty of Pharmacy, Department of Microbiology, Traian Vuia 6, Sect. 2, 020956,Bucharest, Romania. 6“Stefan S. Nicolau” Virology Institute, Bucharest, Romania. FARMACIA 2010; (57); 3: 420-427 IMPACT FACTOR ISI THOMSON 0.144 .

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8. -Aurelian Udristioiu, Radu G. Iliescu, Cristina Popescu. Variability of bilirubin values in serum samples with high triglycerides; interference or congenital liver syndromes. J Biosci Tech Volume 2, Issue 4 (JULY 2011).

9. Aurelian Udristioiu¹*,Radu G. Iliescu², Lucian Udristioiu¹ and Manole Cojocaru. A new approach of abnormal apoptosis as a cause of autoimmunity and malignancy. Biotechnology and Molecular Biology Review Vol. 6(8), pp. 166-171, November 2011 . Available online at < http://www.academicjournals.org/BMBR>

10. Aurelian Udristioiu, Cristina Popescu, Manole Cojocaru, Sorina Comisel, Valentina Uscatescu. Relation between LDH and Mg as Factors of Interest in the Monitoring and Prognoses of Cancer. Journal of Bioanalysis & Biomedicine. Ref.:  Ms. No. JBABM-11-48R1 accepted on Jan 27, 2012

11. UDRISTIOIU A. Florescu C, Popescu C, Cojocaru M "Significance of Neutrophil Alkaline Phosphatase versus Isoenzymes ALP in Acute or Chronic Diseases,"accepted for publication in LabMedicine, LabMedicine Manuscript 11-03-LM-U-MR-0052.R2/11/12/2011.

12. Aurelian Udristioiu¹, Radu Iliescu ², Manole Cojocaru³. Errors in Counting Platelets in Hemodialysis Patients by Use of Optical Microscopy. Review of Applied Physics (RAP) Volume 2 Issue 1, March 2013; p: 17-22

13. Aurelian Udristioiu¹, Radu Iliescu ², Manole Cojocaru³. Energetic Levels of Metabolic Pathways in Malignant B and T Cells Mini-Review. Advances in Chemical Science Volume 2 Issue 4, December 2013; 2; 90-95

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15. Aurelian Udristioiu1*, Radu G. Iliescu2, Manole Cojoraru Molecular mechanisms of bone reconstruction in new dental implant technology. Integrated Journal of British. Volume 1 2014 Issue 1(5-6), pg: 1-7; IJBRITISH.

WRITEN BOOKS:

1.Aurelian Udristioiu. Cicloergometrul si Sanatatea. Ed. Medicala 1990, Bucuresti. ISBN: 973-39-01105-9; Formatul 16/10 x 100; Nr pagini: 78.

2.Aurelian Udristioiu. “Bioenergetica Celulara si Maligna” Ed. Academica Brancusi 2002, Targu Jiu, Bun de tipar, Bucuresti, Tipografia Everest 2001; ISBN 973 85342-6-7; Formatul 16/14 x 100; Nr. Pagini: 307.

3. Aurelian Udristioiu, Manole Cojocaru, Radu Iliescu., Hematological and Metabolic Aspects from Laboratory Medicine" (ISBN 978-3-8473-0775-4). LAP LAMBERT Academic Publishing GmbH & Co. KG Heinrich-Böcking-Str. 6-8 , 66121, Saarbrücken, Germany, 2012.

4. Book title: Renal Diseases / Book 2 (ISBN 979-953-307-704-7). Chapter title: Variability of Biological Parameters in Blood Samples between Two Consecutive Schedules of Hemodyalsis

Authors: Aurelian Udristioiu, Manole Cojocaru, Victor Dumitrascu, Daliborca Cristina Vlad, Alexandra Dana Maria Panait and Radu Iliescu, Publishing Group 2011., Volume 2, Issue 4 (JULY 2011)

5. e-BOOK: Hematological and Metabolical Aspects of Laboratory Medicine (Hematological and Metabolical Aspects from Laboratory Medicine) ( Second Edition ) [Large Print] [Paperback].

 

Publisher: Aurelian Udristioiu, 2 edition (September 9, 2013) Full Color on White paper, 122 pages. ISBN-13: 978-1492186816 (CreateSpace-Assigned) ISBN-10: 1492186813, BISAC: Medical / Laboratory Medicine, USA. Sold by www.amazon.com  

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