Abstract
The word “Apoptosis” or pragrammed cell death is described as the ultimate end of multiple cellular events converging from numerous initiating events to the ultimate death of a cell or organism. Several processes, such as initiation of death signals at the plasma membrane, expression of pro-apoptotic oncoproteins, activation of death proteases, endonucleases etc., that ultimately coalesce to a common irreversible execution phase, lead to cell demise. Counteracting the death signals are cell survival factors. A balance between the cell death and cell survival factors plays a major role in the decision making process as to whether a cell should die or must live. It is, therefore, hypothesized that if the balance can be shifted in favor of cell survival, one might be able to arrest the aging process, save the injured cells or else if the balance is shifted toward cell-kill it might help destroy tumors and other undesirable cells.
Protein A (PA) of Staphylococcus aureus has been found to have multifarious biological response modifying properties. It has been shown to possess anti-tumor, anti-toxic, anti-parasitic and antifungal activities. It also acts as a potent immunostimulator. PA can protect bone marrow progenitor cells from zidovudin(AZT)-induced apoptosis and can stimulate immunocyte proliferation, thereby helping to replenish/restore the depleted hematopoietic cell pool. Such ability to replenish hematopoietic cells is a common property of PA observed against a number of toxic drugs/chemicals, such as cyclophosphamide, benzene, aflatoxin, salmonella endotoxin, etc.
Interestingly, it was further demonstrated in our laboratory that PA can selectively kill tumor cells without affecting normal cells of the host. A search for the mechanisms of PA action revealed that this bacterial protein could shift the balance between pro- and anti-apoptotic proteins in favor of survival in normal cells, but in favor of cell death in tumor cells at a particular dose level. This unique property of PA suggests that controlled use of such type of Biological Response Modifier might help in controlling both cell growth and death phenomena.
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References
Ray PK, Das T. Molecular adaptation to toxic chemicals and drugs. Adv Organ Biol1998;6: 255–269
Cadenas E, Sies H. Oxidative stress: Excited oxygen species and enzyme activity. Adv Enzyme Regul1985;23: 217–237
Arstall MA, Sawyer DB, Fukajawa R, et al. Cytokine-mediated apoptosis in cardiac myocytes: The role of inducible nitric oxide synthase induction and peroxynitrite generation. Circ Res1999; 85: 829–840
Das T, Sa G, Sinha P, Ray PK. Inducation of cell proliferation and apoptosis: Dependence on the dose of the inducers. Biochem Biophys Res Commun1999; 260: 105–110
Sandau K, Pfeilscchifter J, Brune B. Nitric oxide and superoxide-induced p53 and Bax accumulation during mesangial cell apoptosis. Kidney Int1997;52: 378–386
Basu A, Halder S. The relationship between Bcl2, Bax and p53: Consequences for cell cycle progression and cell death. Mol Hum Reprod1998;4: 1099–1109
Wang IK, Lin-Shiau SY, Lin JK. Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells. Pharmacol Toxicol2000;86: 83–91
Rittmaster RS, Thomas LN, Wright AS, et al. The utility of tissue transglutaminase as a marker of apoptosis during treatment and progression of prostate cancer. J Urol1999; 162: 2165–2169
Ding HF, Fisher DE. Mechanisms of p53-mediated apoptosis. Crit Rev Oncol1998;9: 83–98
Pellegrini M, Strasser A. A portrait of the Bcl-2 protein family: Life, death and the whole picture. J Clin Immunol1999;19: 365–377
Waterhouse NJ, Green DR. Mitochondria and apoptosis: HQ or high security prison? J Clin Immunol1999;19: 378–387
Jaattela M. Escaping cell death: Survival proteins in cancer. Exp Cell Res1999; 248: 30–43
Gordon SA, Hoffman RA, Simmons RL, Ford HR. Induction of heat shock protein 70 protects thymocytes against radiationinduced apoptosis. Arch Surg1997; 132: 1277–1282
Jaattela M. Escaping cell death: Survival proteins in cancer. Exp Cell Res1999; 248: 30–43
Loeffler M, Kroemer G. The mitochondrion in cell death control: Certainties and incognita. Exp Cell Res2000; 256: 19–26
TamuraY, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of tumor with autologous tumor-derived heat shock protein preparations. Science1997; 278: 117–120
Achanzar WE, Achanzar KB, Lewis JG, Webber MM, Waalkes MP. Cadmium induces c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis. Toxicol Appl Pharmacol2000; 164: 291–300
Pulverer B, Sommer A, McArthur GA, et al. Analysis of Myc/Max/Mad network members in adipogenesis: Inhibition of the proliferative burst and differentiation by ectopically expressed Mad1. J Cell Physiol2000; 183: 399–410
Chang CC, Liu YC, Cleveland RP, Perkins SL. Expression of c-Myc and p53 correlates with clinical outcome in diffuse large B-cell lymphomas. Am J Clin Pathol2000; 113: 512–518
Wong HR, Ryan M, Menendez IY, Denenberg A, Wispe JR. Heat shock protein induction protects human respiratory epithelium against nitric oxide-mediated cytotoxicity. Shock1997;8: 213–218
Brune B, von Knethen A, Sandau KB. Nitric oxide and its role in apoptosis. Eur J Pharmacol1998; 351: 261–272
Chiu JJ, Wung BS, Hsieh HJ, et al. Nitric oxide regulates shear stress-induced early growth response-1. Expression via the extracellular signal-regulated kinase pathway in endothelial cells. Circ Res1999;85: 238–246
Lin KT, Xue JY, Wong PY. Peroxynitrite. An apoptogenic agent in HL-60 cells. Adv Exp Med Biol1997; 407: 413–419
Samali A, Zhivotovsky B, Jones D, et al. Apoptosis: Cell death defined by caspase activation. Cell Death Different1999;6: 495–496
Nagata S. Apoptotic DNA Fragmentation. Exp Cell Res2000; 256: 12–18
Slavesen GS, Dixit VM. Caspases: Intracellular signaling by proteolysis. Cell1997;91: 443–446
Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science1998; 281: 1312–1316
Sherr CJ. Cancer cell cycle. Science1996; 274: 1672–1677
Peter M, Herskowitz I. Joining the complex: Cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell1994;79: 181–184
Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclindependent kinases. Genes Dev1995;9: 1149–1163
Hall M, Peters G. Genetic alterations of cyclins, cyclindependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res1996;68: 67–108.
Sherr CJ. Cancer cell cycle. Science1996; 274: 1672–1677
Verma AS, Dwivedi PD, Mishra A, Ray PK. Ehrlich's ascites fluid adsorbed over Protein A containing Staphylococcus aureus Cowan I produces inhibition of tumor growth. Immunopharmacol Immunotoxicol1999;21: 89–108.
Shukla Y, Verma AS, Mehrotra NK, Ray PK. Antitumor activity of Protein A in mouse skin model of two stage carcinogenesis. Cancer Lett1996; 103: 41–47
Ray PK, Srivastava M. A new concept in cancer chemoprevention. The Cancer J1996;9: 221–225
Ray PK, Dohadwala M, Bandyopadhyay SK, et al. Rescue of rat from large dose cyclophosphamide toxicity using Protein A. Cancer Chemother Pharmacol1985;14: 59–62
Ghosh AK, Jana S, Das T, et al. Protection by Protein A of apoptotic cell death caused by anti-AIDS drug zidovudine. Biochem Biophys Res Commun1999; 264: 601–604
Das T, Sa G, Ray PK. Mechanisms of Protein A superantigeninduced signal transduction for proliferation of mouse B cell. Immunol Lett1999;70: 43–51
Ghosh AK, Sinha P, Das T., S. aureus superantigen Protein A expand CD4(+)/CD8(+)/CD19(+)/CD34(+) cells in mice: A potential immunorestorer. Biochem Biophys Res Commun1999; 256: 142–146
Ray PK, Goenka S, Das T, et al. Role of nitric oxide in immune function and amelioration of toxicity and carcinogenecity of drugs and chemicals. In: Packer L, Augustine SH, eds. Biological Oxidants: Molecular Mechanisms and Health Effects. USA: AOCS Press 1998: 42–53 Champaign, IL.
Subbulakshmi V, Ghosh AK, Das T, Ray PK. Mechanism of Protein A-induced amelioration of toxicity of anti-AIDS drug, zidovudine. Biochem Biophys Res Commun1998; 250: 15–21
Das T, Sa G, Ray PK. Molecular mechanisms of Protein Ainduced selective apoptosis of tumor cells. The Immunologist1998; Suppl1: 345.
Sinha P, Ghosh AK, Das T, Sa G, Ray PK. Protein A of Staphylococcus aureus evokes Th1 type response in mice. Immunol Lett1999;67: 157–165
Goenka S, Das T, Sa G, Ray PK. Protein A induces NO production: Involvement of tyrosine kinase, phospholipase C and protein kinase C. Biochem Biophys Res Commun1998; 250: 425–429.
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Ray, P.K., Das, T., Sa, G. et al. Protection of apoptotic cell death by protein A. Apoptosis 5, 509–514 (2000). https://doi.org/10.1023/A:1009633412009
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DOI: https://doi.org/10.1023/A:1009633412009