Metastic colon cancer

Abstract

When people first hear the word monoterpene (MT), typically the "terpene" portion conjures up images of some sort of cleaning fluid such as turpentine. Associated with this image is the idea that they are poisons. While the MT's are indeed used as cleaning agents due to their solvent properties, they are far from being poisons. Indeed, nothing could be further from the truth for these naturally occurring and health-promoting substances. While the solvent properties of monoterpenes have been exploited clinically to dissolve gallstones,' the monoterpenes are also the focus of much investigation in the areas of both cancer prevention and therapy. The anticancer properties of the MT's are discussed in the context of clinical data and future directions are explored.

Introduction

Cancer prevention, inhibition, and regression are the most noteworthy attributes of the MT's. D-limonene (DL) and perillyl alcohol (POH) have been shown to be chemopreventive against mammary, [2] liver, lung, UV-induced skin cancer [3] and chemotherapeutic against both experimental mammary and pancreatic tumors. Perillyl alcohol stands out as effective against human pancreatic cancer, [4] colon, liver [5] to reduce vein graft intimal hyperplasia, [6] as chemopreventive against colon carcinogenesis, prostate and lung cancer. [7] Several of these are discussed below in the context of the clinical data.

The Monoterpenes

As seen in figure 1, DL is a monocyclic MT with POH a metabolite of DL, being its hydroxylated form. There are a number of synonyms for limonene, include the following: 1,8(9)p-Menthadiene; 1-methy1-4-(1-methylethenyl) cycloclohexene; 1-methyl-4-isopropenyl-1-cyclo-hexene; alpha-limonene; dipentene; limonene; pmentha-1,8-diene. They are found in essential oils of many plants including lemons, oranges, grapefruit, caraway, dill, bergamot, peppermint, spearmint, grasses and tomatoes. They are also associated with vegetables and some evergreen trees. [8] POH is often distilled from lavender, found in cherries, mint, celery seeds' and can be produced synthetically. It is typically used as flavoring agents, food additive, and fragrance and has been found to be a major volatile component of mother's milk. [8]

D-limonene has different metabolites for different animals. In humans, the three major metabolites after an oral dosage are perillic acid, dihydroperillic acid, and limonene-1,2-diol. It is thought that the metabolic precursors of the first two are perillyl alcohol and perillyl aldehyde. [9] Moreover, many people regularly consume DL everyday without even knowing it. This is because DL is found in things such as orange juice at concentrations ranging from 10-100 ppm and chewing gum, which contains up to 2,300 ppm. [8]

How do they work?

In order to understand the mode of action of the anticancer properties of the monoterpenes, it is necessary to review some of the molecular events that surround cancer. Normal, non-cancer cells live a limited and constrained life. Once normal cells are formed, they have a finite number of cell divisions they undergo during their life-span and, with few exceptions, they remain relatively localized to the same point in the body during this entire process. As a cell lives and ages, it maintains an "awareness" of its surroundings via cell-cell communication molecules both on the cell surface and secreted. This allows the cells to determine if all is well and good and instructs them to maintain their relative positions in the body. Towards the end of a cell's designated life-span, certain cellular events occur which instruct the cell to terminate. This is called "apoptosis" or programmed cell death and is a very normal and useful event for clearing away the old and making room for the new. While it may not sound like the most compassionate thing to do to old cells, the evolutionarily-derived utility of such action affords the body a mechanism to remove cells which might be on their way to becoming cancer cells via mutations.

All cells suffer mutations. These mutations can come as a result of environmental agents, toxic products of metabolism, or arise spontaneously The exact mechanism is not important. What is important, however, is that evolution has built into the cells, mechanisms to deal with these. Apoptosis is one way to get rid of cells which have had everincreasing chances of suffering mutations that are irreparable. The cellular machinery is such that the basal level of mutations are usually successfully corrected by processes such as Nucleotide Excision Repair (NER). [10] When, for various reasons, they cannot be, then generally, apoptosis ultimately will make the mutations moot.

There are several stages in the formation of cancer cells. The first is the initiation stage. During initiation, some mutation has to occur that results in either a loss of function (exemplified by p53, tumor suppressor gene) or a gain of function (e.g., virally derived oncogenes in which there is production of aberrant proteins having normal cellular counter-parts). The key -- mutation needs to occur and not be corrected by the usual cellular mechanism. At this point, cells will typically become described as "immortalized." When this occurs, the cells no longer have finite life-spans, but can live indefinitely. This allows the cancer cells to escape the process of apoptosis. At this stage, the cancer cell is still relatively harmless.

The next stage is the promotion/progression stage of cancer development. Now the cancer cell, usually through a result of even more mutations, becomes "transformed" and no longer acts like a normal cell. The transformed cell is now unrestricted in both its life-span and localization. As stated above, a normal cell will sense its environment and be restricted in its growth. The transformed cell no longer abides by such rules and will multiply, literally piling up on top of its neighbors. Typically, there is an associated perturbation of the cellular glycosylation pattern. [11,12] Also, the morphological structure of the cell itself changes, from being flat with multiple projections, to being much smaller and rounded up.

The final stage is metastasis. Here, the cancer cells have progressed to the point where they are no longer localized to one ever-growing tumor. They gain the ability to enter the blood vessels (intravasation), move to a different location in the body, stop and exit the blood vessel (extravasation) and establish a new site of tumor development. Eventually, the body becomes riddled with tumors consuming the bulk of available energy. The body is literally eaten alive as evidenced by the cancer-associated cachexia (body wasting).

In that dreadfully bleak picture of cancer development, there are some shining points of lights. The MT's, found in essential oils, are such points of light, offering some hope in the struggle to prevent and treat cancer. The best news is that DL and POH can not only prevent but also treat cancer. That is to say, the MT's can act before a cancer is established and in the cases where cancer is already present, they can cause a regression of the tumor, oftentimes completely. In fact, levels of tumor regression as high as 81% have been achieved for small mammary carcinomas and up to 75% for advanced mammary carcinomas. [22] They do this in at least six ways. First, during the initiation phase of carcinogenesis they induce (cause the body to make more of) Phase I and II carcinogen-metabolizing enzymes, resulting in carcinogen detoxification. [13] An example of such a Phase II enzyme would be glutathione S-transferase. [14] Second, post-initiation phase, they have been shown to increase cell redifferentiation. Thi s causes the potential cancer cells to take on a more normal morphology. Third, they can induce apoptosis in otherwise immortalized (see above) cells. Fourth, they have been shown to inhibit the isoprenylation [15] of the cellular products (Ras [16]) of oncogenes. Simply put, the proteins from oncogenes, which on the whole are cell-growth regulating proteins, need to be modified (referred to as "post-translational modification") by a process called prenylation in order to be placed in a membrane where they are active. If the proteins from oncogenes do not undergo isoprenylation, they do not cause the cell to behave as a cancer cell and hence cancer inhibition results. It is believed that this prenylation inhibition occurs at both the farnesyl and geranylgeranyl transferases. Fifth, MT's have been shown to inhibit the conversion of lathesterol to cholesterol, resulting in positive therapeutic results due to the fact that many tumor cells are deficient in oxidative phosphorylation and use glycolysis as the sole energy source. [22] Sixth, the MT's have been shown to enhance activation of inhibitory growth factors such as TGF[beta], which has been suggested to potentially inhibit breast cancer cells. [23]

Clinical data