The steady state of a normal tissue, or a tumor cell, is a balance between new cells acquired from mitotic division of precursor cells with the attrition of cells through apoptosis or programmed cell death. Apoptosis occurs when physiologic signals trigger a defined series of cellular changes resulting in disruption of the cellular membrane, disintegration of the cytoskeleton, extrusion of cytosol, degradation of chromosomes, and fragmentation of the nucleus.26 This process induces cell destruction without the inflammatory responses characteristic of cell necrosis.23 Although almost all cell types in the body have the capability to undergo apoptosis under appropriate developmental circumstances, apparently most, if not all, types of cancer cells acquire the capability to evade apoptosis, making activation of apoptosis a chemopreventive and therapeutic target.
Two families of membrane-associated death receptors are known. One is the FAS-receptor and another related set includes the tumor necrosis factor (TNF) and TNF-related apoptosis inducing ligand (TRAIL) receptors.23 Several proteins have been identified to be intrinsic to the apoptotic pathway. Bcl-2 (and related proteins Bcl-XL and Bcl-W) is an oncogenic protein that protects cancer cells by inhibiting apoptosis. Opposing Bcl-2 is Bax (and related proteins Bak, Bid, and Bim), which competes with Bcl-2 and acts as an inducer of apoptosis.26 Upon sensing DNA damage, the p53 tumor suppressor protein elicits apoptosis by upregulating the expression of proapoptotic Bax, which then stimulates mitochondria to release cytochrome C and initiate programmed cell death. The ultimate effectors of apoptosis include the family of intracellular proteases, the caspases. Caspase-8 is activated by death receptors including FAS, and caspase-9 by cytochrome C released from mitochondria.26 A number of other proapoptotic and antiapoptotic components are also involved; the complexity of this apoptotic signaling network is depicted by Gosslau and Chen.37
A plethora of natural compounds have been identified that can induce apop-tosis by a number of different mechanisms. These include increasing signals to promote cell death (i.e., Bax) and by decreasing signals inhibiting cell death (i.e., Bcl-2). Death signals can be increased by cellular damage (at least in vitro), increased function of p53, and increased activity of antigrowth factors such as TGF-p. The opposing strategy involves inhibition of survival factors, including growth factors and their signaling pathways.36 The proapoptotic effects of res-veratrol have been extensively reviewed.38 These effects include effects on induction of death receptors, activation of the mitochondrial pathway, effects on Rb phosphorylation, activation of p53 pathway, generation of the proapoptotic mediator ceramide, and more. Other phytochemicals that can induce apoptosis include lycopene and P-carotene, a number of flavonoids, the allyl-sulfur compounds of garlic, caffeic acid phenethyl ester from honeybee propolis, and curcumin.37
Normal cells in culture have a finite replicative potential. When these cell populations proceed through a set number of doublings, they undergo senescence, or a cessation of growth and eventually death via apoptosis. This process operates independently of the cell-to-cell signaling involved with proliferation and apop-tosis. Cultured tumor cells are immortalized and exhibit limitless replicative potential. This suggests that, with the genetic changes occurring during the process of carcinogenesis, cells acquire traits resulting in a breach of the mortality barrier. The counting device for tallying replications has been found to be the ends of the chromosomes, called telomeres. With every replication, 50 to 100 base pairs are lost from the telomeres, until the unprotected chromosomal ends become involved in chromosomal aberrations and karyotypic disarray, stimulating cell death processes.23 However, in nearly all malignant cells, telomeres are maintained through the action of telomerase, which adds nucleotides onto the ends of telomeric DNA. Human telomerase is composed of template RNA components and two proteins, telomerase-associated protein-1, and telomerase reverse transcriptase (hTERT), which are thought to be the enzyme's catalytic subunit.39 Most human somatic cells do not have detectable telomerase activity and lack activity of hTERT. However, immortalized cells express hTERT and have detectable telomerase.23
Tumor growth is thought to require activation of telomerase, making it a target for chemoprevention.39 Retinoids induce senescence in malignant and pre-malignant human and rat breast carcinoma cells, in vitro and in vivo.40 Retinoids also synergize with vitamin D in inhibiting telomerase. The combination of vitamin D3 and 9-cis-retinoic acid inhibited telomerase activity through direct interaction of the heterodimer of the vitamin D3 receptor and retinoid X receptor (RXR) in prostate cancer cells.41 Other nutritional factors, including EGCG and curcumin, also regulate telomerase activity. In nude mice models bearing both telomerase-dependent and -independent xenograft tumors cloned from a single human cancer progeny, only the telomerase-dependent tumors responded to prolonged oral administration of EGCG.42 Furthermore, curcumin inhibits telomerase activity in MCF-7 breast cancer cells via downregulation of hTERT expression.43
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