Cancer is one of the predominant killers in the western world today. Despite much advancement in cancer therapy, many cancers are still ineffectively treated or become resistant or recur. In addition, the methods of treating cancer are often difficult for patients to tolerate due to the side effects. Thus, there continues to be great interest in the search for new and better treatments. Plant-based medicines have definitely found a role in this type of treatment and the mechanism of interaction between many phytochemicals and cancer cells has been studied extensively.
In order to understand phytochemical-cell interactions it is first important to understand a little about the life cycle of human cells, including proliferation, differentiation, and cell death. The cell reproductive life cycle has four phases: (see Figure 5.1) Gt, S, G2, M. G0 is a stage of quiescence which can be of variable length. During this time the cell is carrying out its ordinary role for the organism. If there is a commitment to proliferation, then purines and pyrimidines, the building blocks for DNA synthesis, must be produced. The cell then enters the
Cell Life Cycle
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G1 state in which nucleotides and enzymes are synthesized. In the S phase DNA synthesis occurs. Many enzymes must work together to reproduce an accurate replication of DNA for the new cell. One enzyme of this system that seems to be particularly vulnerable to exogenous plant chemicals is topoisomerase. Its job is to separate the daughter DNA strands. The next phase is G2 when the cell prepares other structures needed for mitosis. The M phase is mitosis itself and the production of two daughter cells which will then enter the cycle themselves.
In most cell systems there is a period of normal growth which is a time of proliferation of cells. With more maturity of the tissue, the cells differentiate into the various specialized subsets required for tissue function. These differentiated cells no longer proliferate, instead they synthesize the proteins, steroids, and other chemicals required for maintenance or function of the organism. Within the tissue there remain stem cells capable of proliferation. In some areas such as bone marrow (where blood cells form), skin, and the lining of the gastrointestinal tract, there is a high turnover of cells. This requires a high density of stem cells and constant proliferation.
Cancer cells can be thought of as cells that become capable of proliferation. Much work has been done to identify oncogenes and tumor suppressor genes which are thought to control this abnormal proliferative state. One recent approach to therapy has been to try to induce cells to differentiate into more specialized cells and, therefore, stop proliferating.
Although stem cells and cancer cells may be nearly immortal due to their proliferative capacity, cell death does occur. Necrosis is the process of cell death due to external events such as hypoxia, chemical exposure, radiation injury, and many others. Cells are observed to swell, become vacuolized, and finally be digested by either their own enzymes or the enzymes of neutrophils. The critical insult is to the cell membranes, through lipid peroxidation. This causes permeability changes and allows massive influx of calcium ions. Excess calcium ions inactivate mitochondria and denature proteins and enzymes. Necrosis generally occurs in contiguous cells and is accompanied by an inflammatory response. Many currently available cancer treatments induce necrosis.
In contrast to necrosis, apoptosis is programmed death, whereby physiologic signals, such as hormones or growth factors, trigger rapid DNA damage, condensation of chromatin, and fragmentation of DNA. The cell, too, becomes fragmented and is phagocytized by nearby macrophages or neutrophils without causing inflammation. Several chemotherapeutic agents that cause DNA damage also lead to apoptosis. Recent research has looked more seriously at apop-tosis as a goal of chemotherapy. Some natural agents may have more application in this area.
In the section which follows we will highlight some of the plant chemicals which are currently in use as anticancer agents or which are being studied for their potential application. We will not attempt an exhaustive coverage of this field but rather a representative one. In turn, these examples will illustrate some of the ways phyto-chemicals interact with mammalian or human cells.
Epidemiological studies have shown that populations that have a high soy intake have a lower incidence of breast and prostate, as well as other carcinomas. Genistein is an isoflavone (Figure 5.2) found in high quantities in soybean products. Genistein-containing soy diets have been shown to decrease incidence and number of tumors, and to increase latency in animal models of cancer.1 Much work has been done in cell-culture models which demonstrate that genistein inhibits proliferation of some types of cancer cells.2 Cell culture and other in vitro techniques have been used to elucidate the mechanism by which genistein might alter cancer cell kinetics. There is evidence to support several hypotheses of the target site and mechanisms of action of genistein. Some of these are inhibition of angiogenesis,3 interaction with steroid hormone receptors, inhibition of tyrosine kinase, inhibition of radical oxygen species formation, and interaction with topoisomerase.24 In this section, we will focus on the interaction with topoisomerase which appears to be one of the more important mechanisms in regulating cellular proliferation.
DNA in its resting state (does it ever really rest?) is highly twisted to conserve intracellular space. In order for transcription to occur, the DNA must be relaxed. The topoisomerase enzymes relax the DNA by nicking single strands. This allows normal gene expression to occur and cells to proliferate. Genistein is postulated to stabilize the enzyme/DNA complex in such a way that both strands are nicked and DNA breaks occur. Hypothetically this leads to altered gene expression and cell differentiation and a concomitant decrease in cell proliferation. Experiments have shown that at genistein concentrations high enough to induce cell differen-
tiation, all types of cells tested had extensive DNA breakage. In a cell-free system containing supercoiled plasmid DNA and genistein, linear DNA (i.e., broken DNA) was produced only when topoisomerase II was present. This supports topoisomerase as the active site for genistein.5 Further support comes from other experiments where cell lines were developed that were resistant to the effects of genistein. Resistant cells showed altered activity of topoisomerase II6 or markedly reduced expression of the topoisomerase II ß isoform.7 Because of genistein's site of activity, it will be further tested as an anticancer agent. Soy products, in general, are an important part of a diet to promote wellness.
Several anticancer agents create their effects by interrupting cell division. Since cancer cells are dividing at a more rapid rate than the normal cells around them, the chemotherapeutic agents have a proportionally greater impact on the tumor cells. The target site for the taxoids and the well-known Vinca alkaloids is microtubule formation. Microtubules are critical to spindle and aster formation in all cells as they prepare for mitosis. Microtubules also have other cellular functions, such as maintenance of cell shape, cellular motility and attachment, and intracellular transport. Tubulin dimers polymerize to form microtubules. This is in dynamic equilibrium controlled according to the cell's needs by intracellular messengers, such as calcium and guanosine triphosphate (GTP).8
The Vinca alkaloids, vinblastine and vincristine (Figure 5.3), are derived from the periwinkle (Catharanthus roseus). They have been used for many years in treating lymphomas and acute childhood leukemia, respectively. Vincristine and vinblastine inhibit cancer cell reproduction by promoting microtubule disassembly. They bind to the tubulin dimers. When the tubulin-alkaloid complex attaches to the microtubule, polymerization is terminated and depolymerization begins. Mitosis is arrested at metaphase.9
The taxoids, paclitaxel and the related semisynthetic docetaxel, are examples of novel new anticancer agents provided by plants. Paclitaxel is extracted from the bark of the Pacific yew (Taxus brevifolia), as well as needles and stems of other yews (Taxus spp). Docetaxel is derived from a precursor, baccatin III, found in the needles of the English yew (Taxus baccata L.).
In contrast to the Vinca alkaloids, paclitaxel and docetaxel (Figure 5.4)
induce assembly of microtubules and stabilize microtubule networks. Cells treated in vitro with paclitaxel form disorganized bundles of microtubules in all phases of the cell cycle. During cell division, paclitaxel induces the formation of many abnormal spindle asters. Cells are either arrested in mitosis or in G or S phases. Docetaxel has twice the potency of paclitaxel in inducing microtubule polymerization. Treated cells accumulate in the mitotic phase of the cell cycle.10 The taxoids are being used successfully in refractory ovarian cancer,11 breast cancer, and non-small-cell lung cancer. Their side effect profile is largely pre dictable from the mechanism of action. Normal body cells with a high turnover or with processes dependent on microtubule formation, such as white blood cells, gastrointestinal mucosa, neurons, and secretory cells are preferentially incapacitated to some degree by paclitaxel and docetaxel. These effects are generally reversible and dose schedules have been developed to maximize tumor response and minimize side effects. Overall cancer response rates have varied from 30 to 70%. These taxene compounds are and will continue to be important anticancer agents, particularly if supply problems are solved (see other chapters in this work).81011
Chinese traditional medicine has been preserved, respected, and incorporated into the modern approach in that country. Many of the plants used in that system have potential anticancer efficacy. The bark of the Chinese evergreen, Cephalotaxus harringtonia, is used for several indications, including treatment of malignancy.12 The alkaloids extracted from the seeds of this tree were tested in the National Cancer Institute (NCI) screening program of the 1960s and shown to have cytotoxic activity. There are several related active substances, all of which are esters of the alkaloid, cephalotaxine.
Homoharringtonine (HHT) (Figure 5.5) is the most active of the alkaloids. Further testing in animal models confirmed its ability to prolong the life of animals bearing implanted tumors. HHT is now in phase II and phase III trials in humans for treatment of acute nonlymphoblastic leukemias and chronic myelogenous leukemia. The initial results are promising.13
HHT has its cytotoxic effects in the G1 and G2 phases of the cell cycle.14 These are the times of intense protein synthesis. Protein synthesis involves two major steps: initiation and elongation. During initiation the messenger ribonucleic acid (mRNA), bearing the code for the new protein, associates itself with the ribosome. The first transfer RNA (tRNA) then attaches to the mRNA, bringing the initial amino acid building block for the protein. Elongation is the process by which subsequent tRNA's attach to the mRNA and bonds are formed between the amino acids to produce the polypeptide protein. HHT inhibits the elongation step, most likely not from inhibiting the bonding of tRNA to mRNA, but by competitively inhibiting the enzyme, peptidyl transferase, which catalyses the formation of the polypeptide bond.13 There is evidence that HHT also disrupts protein synthesis in other ways, such as detaching ribosomes from endoplasmic reticulum, degrading ribosomes, inhibiting release of completed proteins from ribosomes, and inhibiting glycosylation of completed proteins.13 Through these mechanisms HHT may induce both apoptosis and differentiation of cancer cells, making it an important new anticancer agent.
Rhein is an anthraquinone found in rhubarb (Rheum spp.) and other purgatives (Figure 5.6). Rhein is also antineoplastic. Several hypotheses exist as to the mechanism of action by which rhein exerts its antitumor effects. Studies show that it exerts an effect at the membrane level. In electron microscopic evaluation, rhein appears to distort and disrupt the membranes of both mitochondria and cells. Membrane disruption appears to be mediated through altered actin microfilaments, which collapse into ring-like structures in the cell cytoplasm. In addition, the christae of mitochondria are disrupted. This may lead to impairment of energy metabolism, variations in cellular permeability, and altered receptor molecule activity.15 Others have hypothesized that rhein alters the fluidity of membranes and hence the uptake of glucose.16 The net result is decreased energy available for vital cellular functions and eventual cellular necrosis. Because of rhein's proposed mechanisms of action, it is a phytochemical that may warrant further examination as an antineoplastic agent.
FIGURE 5.6 Chemical structure of rhein anthraquinone, an anticancer drug found in rhubarb (Rheum spp.).
ort o M Rhein Brtthraquinwra
Mistletoe, well known for its amorous seasonal effects, is also well known in Europe as an adjuvant cancer therapy. Aqueous extracts of Viscum album L. are used for their combined effect as immunostimulatory and cytotoxic agents. The polysaccharide portion of the extract is thought to be responsible for the immunostimulatory effects, much in the same manner as Echinacea polysac-charides (see Section 5.4.2). Recent work has focused on the lectin portion of mistletoe extract. Lectins are proteins that cause agglutination and mitoses of mammalian cells. Studies with tumor cell lines in vitro show that mistletoe lectins inhibit tumor growth. Further analysis indicates that the DNA in these cells is fragmented as would be expected in apoptosis.17 Other researchers found evidence of both membrane damage leading to necrosis and DNA damage indicative of apoptosis.18 It may be that mistletoe extracts or purified mistletoe lectins will be validated with further studies as an effective means of treating some cancers.
In this section we have seen how phytochemicals interact with various parts of the human cell life cycle (see Figure 5.7). These mechanisms can be employed to target rapidly proliferating tumor cells and to induce differentiation, apop-tosis, or necrosis. The Vinca alkaloids and the taxoids are currently used in mainstream cancer treatment. Homoharringtonine is in human trials to determine dosage schedules and effects on a broad population. Genistein, mistletoe, and rhein are promising in their mechanisms, but work remains to be done before they will be approved for use in the U.S. Opportunities for research abound in these important applications of phyto-chemicals to the cancer epidemic of our current times.
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