Title: Apoptosis

Key words: Cancer, cell death, programmed cell death, cell damage, cellular homeostasis

Date: Feb 1999

Category: 1. The Cell

Type: Article

Author: Dr van Rhijn

 

 

Apoptosis

 

Health Implications of Long-term Administration of Natural Compounds

 

 

 

Introduction

Apoptosis is a cellular control mechanism of programmed cell death (PCD), to remove potentially harmful cells, during development (faulty1 or excess cells), maintenance of tissue homeostasis (regression of proliferation), in defence against cancer and virally infected cells and in ageing (cell damage). Although apoptosis can be induced or prevented by numerous mechanisms, this paper will focus on the effects of natural compounds and their implications for human health.

 

Mechanism of Apoptosis

The cell death mechanism (withdrawal of life signals2) of apoptosis is clearly distinct from necrosis. In necrosis, the cellular contents are released, potentially imposing oxidative stress on the surrounding tissues3. In apoptosis, in contrast, cells do not release their contents and so do not cause local disruption or inflammation. A variety of key events in apoptosis focus on mitochondria, and damage can lead to a cascade of caspase4, 5 activators (such as cytochrome C)6 and subsequent protein degradation, which can be blocked by dithiocarbamates7. Studies suggest that oxidant stress, increased ROS7 and long-lasting nitric oxide (NO) generation8, antioxidant depletion or the pro-oxidant action of ascorbate9 may induce apoptosis, which can be blocked or slowed by antioxidants.

 

Natural Compounds and Apoptosis

Naturally occurring phenolic compounds in food (caffeic, ferulic and p-coumaric acids) exhibit potent cytoprotective (anti-apoptotic10) effects on cultured endothelial cells by delaying LDL oxidation. Curcumin and gallic acid act as cytotoxic11 agents (radical scavengers) and induce apoptosis in human cancer cells. Glucocorticoids12 appear to be some of the best inducers of gene expression and apoptosis, which may be inhibited by zinc13, via modulating protein kinase C14, 15 activity.

 

The natural dietary flavone, genistein16, has pronounced antiproliferative effects on both oestrogen receptor-positive and -negative human breast carcinoma cells. Two natural oncostatic agents, melatonin and retinoic acid17, have been shown to inhibit neoplastic cell proliferation of hormone-responsive breast cancer. Natural phytochemicals18 inhibited proliferation in non-cancerous human mammary epithelial 184-B5 cells (Benzo (a) pyrene (BP)-induced aberrant) in part due to regulation of cell cycle progression and induction of p53 dependent apoptosis. Numerous other compounds, such as glutamate, toxins (ethanol, dioxins), puromycin and mycotoxins19, have been associated with apoptosis.

 

Health Implications

Metabolic disturbances of initiation and/or realisation20 of PCD make a substantial contribution to a number of pathologies. Inhibition of apoptosis is associated with diseases such as various cancers (p53 mutations), autoimmune disorders, and viral infections (AIDS), whilst increased apoptosis with cardiovascular and neurodegenerative disorders (dopamine in Parkinson’s21), ischaemic injury, myelodysplastic syndromes, toxin and drug induced conditions. The human food chain is constantly exposed to new compounds, which poses a potential health risk. Long-term administration may promote and maintain chronic diseases and cancer. It is vital to remain vigilant and avoid compounds that will challenge the delicate apoptotic mechanism beyond its ability to maintain homeostasis.

 

Conclusion

The understanding of the complexity of apoptosis is still in its infancy, but it is becoming obvious that various environmental compounds influence and disturb this vital, sensitive inner control mechanism. Ongoing research is required to find natural adjunct therapies, able to induce or inhibit apoptosis as required, to reduce the morbidity and mortality of chronic diseases.

 

 

 

References

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2.      Jacobson, M.D. POS and programmed cell death. Trends Biochem. Sci. 1996; 21: 83.

 

3.      Halliwell, B and Gutteridge, J. M. C. Free radicals in Biology and Medicine. 1999; Oxford University Press. 3rd Edition. 

 

4.      Cohen, G.M. Caspases: the executioners of apoptosis. Biochem J. 1997; 326, 1.

 

5.      Hampton, M.B. and Orrenius, S. Dual regulation of caspase activity by H2O2: implications for apoptosis. FEBS lett. 1997; 414, 552.

 

6.      Green, D.R. and Reed, J.C.  Mitochondria and apoptosis. Science, 1998; Aug 28, 281:5381, 1309-1312.

 

7.      Nobel, C.S.I. et al. Mechanism of dithiocarbamate inhibition of apoptosis. Chem. Res. Toxicol. 1997; 10, 636.

 

8.      Brüne, B. et al.  Apoptotic cell death and nitric oxide: activating and antagonistic transducing pathways. Biochemistry (Mosc), 1998; Jul, 63:7, 817 – 825.

 

9.      Sakagami, H. and Satoh, K. Modulating factors of radical intensity and cytotoxic activity of ascorbate. Anticancer Res, 1997; Sep, 17:5A, 3513 – 3520.

 

10.  Vieira, O. et al. Effect of dietary phenolic compounds on apoptosis of human cultured endothelial cells induced by oxidized LDL. Br. J. Pharmacol. 1998; Feb, 123:3, 565 - 273.

 

11.  Nogaki, A. et al. Radical intensity and cytotoxic activity of curcumin and gallic acid.   Anticancer Res.; Sep, 18:5A, 3487 - 3491.

 

12.  Hofmann, T.G. et al.  Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kappa B-dependent transcription. FEBS Lett. 1998; Dec 28, 441:3, 441 - 446.

 

13.  Zalewski, P.D. et al.  Flux of intracellular labile zinc during apoptosis (gene-directed cell death) revealed by a specific chemical probe, Zinquin. Chem. Bio. 1994; 1: 153 – 161.

 

14.  Forbes, I.J. et al. Interaction between protein kinase C and regulatory ligand is enhanced by a chelated pool of zinc. Biochem. Biophys. Acta. 1990: 1053: 113 – 117.

 

15.  Thompson, C.B. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267: 1456 – 1462.

 

16.  Shao, Z.M. et al.  Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res. 1998; Nov, 58:21, 4851 - 4857.

 

17.  Eck, K.M. et al.  A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. Br. J. Cancer. 1998; Jun, 77:12, 2129 – 2137.

 

18.  Katdare, M. et al.  Inhibition of aberrant proliferation and induction of apoptosis in pre-neoplastic human mammary epithelial cells by natural phytochemicals. Oncol. Rep. 1998; Mar, 5:2, 311-315.

 

19.  Wang, W. et al.  Fumonisins and Alternaria alternata lycopersici toxins: sphinganine analogue mycotoxins induce apoptosis in monkey kidney cells.  Proc. Natl. Acad. Sci. U S A. 1996; Apr, 93:8, 3461 – 3465.

 

20.  Khanson, K.P. Apoptosis: current status of the problem. Izv. Akad. Nauk. Ser. Biol, 1998; Mar 2, 134 – 141.

 

21.  Offen, D. et al. Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2.  Cell Mol Neurobiol. 1997; Jun, 17:3, 289 - 304.