How Natural Compounds And Chemotherapy Drugs Inhibit Proliferation

Let us now pull together what has been presented about how natural compounds inhibit cancer cell proliferation and compare how natural compounds work to the way current chemotherapy drugs work, thus clarifying what natural compounds have to offer. As we will see, the cancer inhibitory effects of most natural compounds discussed are not due to direct DNA damage, whereas direct DNA damage is an important mechanism for many of the chemotherapy drugs used today. This distinction is important, in that natural compounds are therefore less likely than many chemotherapy drugs to induce DNA mutations in surviving cells. Moreover, natural compounds are more likely to act selectively on cancer cells and spare normal cells than are most chemotherapy drugs now in use.

Targets of Natural Compounds Versus Targets of Chemotherapy Drugs

Targets of Natural Compounds

Cancer cells can be likened to drug addicts. They need a regular fix to keep them going, and without it, they fall apart. Their fix is the abnormally high throughput of proliferation signals (and "do not die" signals). Without these signals, some cancer cells enter a quiescent period, and many, unable to survive without a fix, die via apop-tosis. Normal cells, which do not depend on such a high throughput of signals (or self-originated signals), tend to be less susceptible. The natural compounds discussed here tend to inhibit the proliferation of cancer cells by removing the flow of signals that leads to cell proliferation and prevention of cell death.

Since cancer cells and normal cells work by the same mechanisms, the flow of signals that instructs both to proliferate is the same, except in cancer cells the signals are more abundant and also largely self-originated. Therefore, if we were to eliminate these signals, normal cells would also suffer. The natural compounds I discuss do not have this strong an effect, however. Instead, at the plasma concentrations that are achievable with oral administration, they tend to reduce the signal flow to more normal levels.

The flow of information leading to cell proliferation is mediated through proteins, as illustrated in Figure 2.7. In the figure, abnormal gene expression is the most prominent feature, since such expression is central to the proliferation and malignant behavior of cancer cells. As shown, abnormal gene expression results in one of four types of protein signals that assist proliferation or malignant behavior. All four of these primary protein signals can be inhibited by natural compounds.

1. Errors in the p53 gene can produce p53 proteins that fail to induce apoptosis in cells with DNA damage, resulting in increased DNA instability and unchecked proliferation. Errors in the Bax gene can produce proteins that also fail to induce apoptosis in cancer cells. Errors in the Bcl-2 gene can produce excessive amounts of proteins that protect against apoptosis in cancer cells.

2. Abnormalities in some genes can produce excessive amounts of proteins that assist angiogenesis (the growth of new blood vessels), or assist in invasion, metastasis, or evasion of the immune system. Although these do not have direct effects on proliferation, they do affect proliferation or the rate of cell death indirectly.

3. Overexpression of oncogenes such as fos, jun, and myc can produce large amounts of fos, jun, and myc proteins. As discussed above, these proteins act as transcription factors to induce the expression of genes such as cyclin genes, whose proteins drive the cell cycle proper. In addition, overexpression of cy-clin genes can directly produce excessive amounts of cyclin proteins.

4. Abnormal genes can produce several proteins that facilitate signal transduction. These proteins include growth factors, growth factor receptors, and kinase enzymes, ras proteins, and others. (These are discussed in Chapter 4.) Overproduction of these proteins results in increased signal transduction, which stimulates abnormal activity of transcription factors such as AP-1 and NF-kB (discussed in Chapter 5). Abnormal transcription factor activity stimulates gene expression, resulting in the overproduction of cyclin proteins that drive the cell cycle and the overproduction of other proteins that assist angiogenesis, invasion, and metastasis.

Figure 2.7

The Flow of Protein Signals Leading To Cancer Cell Proliferation compounds that cause classical mutations or epigenetic changes

instability or alterations

Figure 2.7

The Flow of Protein Signals Leading To Cancer Cell Proliferation compounds that cause classical mutations or epigenetic changes

instability or alterations

abnormal production of growth factors, their receptors, or other proteins (e.g., ras proteins)

that assist in signal transduction errors in proteins that repair DNA (e.g., p53) or induce apoptosis

(e.g., Bax) proteins that assist angiogenesis, invasion metastasis, and/or immune suppression abnormal production of growth factors, their receptors, or other proteins (e.g., ras proteins)

that assist in signal transduction failure of repair proteins to stop the cell cycle (e.g., p53)

abnormal production of transcription factors that initiate proliferation (e.g., fos and jun)

excessive signal transduction abnormal gene expression excessive production of proteins that control the cell cycle (e.g., cyclins)

abnormal activity of transcription factors that initiate proliferation (e.g., AP-1, NF-kB)

excessive proliferation

Natural compounds that inhibit these signals are discussed in Chapters 3 through 6. Their actions include lowering mutation rates by scavenging free radicals, normalizing p53 activity, or both; inhibiting abnormal transcription factor activity; inhibiting kinases or other proteins involved in signal transduction; inhibiting the activity of cyclin proteins, which drive the cell cycle; and increasing cell-to-cell communication, which sends signals that normalize gene expression.

Natural compounds that inhibit signal transduction can play a dual role in inhibiting cancer. In addition to proliferation signals, cancer cells (like normal cells) also require "do not die" signals to prevent death through apoptosis. In cancer cells, these signals come in part from both growth factors and increased signal transduction. Therefore, natural compounds that reduce signal trans-duction not only can inhibit proliferation but can also induce cell death.

Targets of Chemotherapy Drugs

In contrast to natural compounds, the chemotherapy drugs in current use primarily target DNA. Several aspects of DNA are targeted, including the structure of individual nu-cleotides; the integrity of nucleotides or their bases within DNA; the main enzymes active in the synthesis phase (DNA poly-merase and topoisomerases, which are active in DNA replication and in DNA unwinding, respectively); and the structures and enzymes active in the mitosis phase. By acting on these targets, these drugs prevent completion of the cell cycle. Their actions do not target cancer cells specifically but inhibit the proliferation of any cell in the cell cycle. This means that normal cells frequently in the cell cycle, such as hair cells, immune cells, and cells of the gastrointestinal lining, are harmed along with cancer cells. To give a clearer idea of how these drugs work, we consider these targets in more detail, starting with those that target nu-cleotide structure.

Targeting Nucleotides Structure

One way of inhibiting cancer cell proliferation is to inhibit the production of nucleotides. A number of chemotherapy drugs, classified as antimetabolites, act by this means. For example, folate, a B vitamin, is needed for the synthesis of some bases. Drugs such as meth-otrexate inhibit folate activity. Other drugs like fluorouracil, hydroxyurea, and cytarabine inhibit DNA synthesis in other ways. The latter inhibits DNA polymerase, the enzyme that makes new strands of DNA during replication. To some degree it also substitutes the sugar arabinose for ribose during DNA synthesis (functional nucleotides contain ribose).

Targeting Nucleotides Within DNA

A number of chemotherapy drugs act by altering the nucleotides within DNA once it is formed, thereby damaging the DNA and inhibiting its replication and transcription. Some drugs—for example, cyclophospha-mide, carmustine, cisplatin, mitomycin, and busulfan— are alkylating agents, which means they add strings of hydrocarbon molecules to the nucleotides. These strings can bind DNA strands together or simply hang on single DNA strands, thereby interfering with DNA replication, transcription, or repair.

Other chemotherapy drugs, such as doxorubicin and bleomycin, are intercalating drugs, meaning they insert themselves between adjacent DNA base pairs. The flat structure of these drugs allows them to slip easily between base pairs. Some of these drugs, including doxorubicin and bleomycin, instigate free radical damage to bases once they are inserted. Intercalating drugs interfere with both DNA and RNA synthesis.

Targeting Topoisomerases

Topoisomerases are enzymes that unwind the DNA so that both DNA replication and gene transcription can take place. Some chemotherapy drugs, such as the natural compound camptothecin and the semisynthetic compound etoposide, act via topoisomerase inhibition.

Some natural compounds discussed here also have the capacity to inhibit topoisomerases. These include api-genin, ATRA (vitamin A), boswellic acid, genistein, luteolin, and quercetin (see Appendix C for details). These compounds are active in the concentration range of roughly 1 to 200 mM, with the IC50 for most of them tending to be greater than 30 mM. Two exceptions are boswellic acid and ATRA, which are reportedly active at concentrations between about 1 and 10 mM. This concentration of ATRA is similar to peak plasma concentrations normally produced during ATRA treatment of leukemia patients after high doses. All of these compounds, however, also inhibit cancer through other mechanisms and usually at lower concentrations than those just discussed. Therefore, topoisomerase inhibition is not likely to be a primary mode of cell inhibition for any of these compounds in vivo (after oral administration); other anticancer actions are likely to take precedence.

Targeting Mitosis

Compounds that inhibit the mitosis (M) phase in the cell cycle, called antimitotic compounds, prevent cell proliferation. Some chemotherapy drugs that are themselves natural compounds act as antimitotics, including vincristine and vinblastine. The natural compounds discussed in this book do not generally act in this way, however.

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