Cancer and Fat Metabolism
The case for Carnitine Supplementation
Bob Berger, MS, MVSc, PhD
Although much is known and has been studied concerning carnitine status (i.e., the physiological values of carnitine and carnitine fractions in the blood, tissues, and excretions), in the body of healthy individuals as well as in those who present specific metabolic/organic disease, this subject has never been fairly treated in any significant considerable depth as a “high profile” factor of health status; but, in reality, it truly should be.
The metabolism/utilization of long-chain fatty acids, derived from the breakdown of fat and are required for the majority of ATP[energy] produced (which we need to stay alive), requires carnitine; specifically, the physiologically active form; L-carnitine. Describing this process in more simple terms, L-carnitine (3-hydroxy-4-N-trimethyl-aminobutyrate), is a quaternary ammonium, amino acid complex, required for shuttling both endogenous-and/or exogenous-derived long-chain fatty acids (from lipid breakdown), through the mitochondrial membrane into the mitochondrial matrix, where fat oxidation and aerobic (O2) energy production takes place.
Since the mitochondria is the “powerhouse of the cell” (where all the aforementioned aerobic (O2) oxidation takes place), without the availability of L-carnitine, the energy derived from oxidation of long-chain fatty acids (i.e., via βeta-[β-]oxidation), would not take place.
The first thing to understand is exactly how important carnitine is for cellular energy…without it, either being synthesized endogenously or retrieved exogenously from food sources, [such as from meats (where the name “carni” and/or “carnivorous” comes from), or from specific foods, such as the avocado (the only fruit which contains carnitine)], we would be essentially losing all the energy which is provided by long-chain fatty acids. One of these long-chain fatty acids, for instance, is palmitic acid, the 16-chain-length fat which provides us with the majority of energy we get from food, which is responsible for considerable ATP production.
The second thing to understand is that cancer strips away energy from its victims. A neoplasm uses the energy, which is meant for normal, healthy cells to utilize, instead, for cancer cells to multiply, grow, and spread. As cancer cells divide many times more rapidly than do normal cells, they use up this energy before the normal cells are able to use it; thus, malignant cell growth is supported while normal cell growth is inhibited; and the normal, once healthy cells, eventually die…this is one of the ways cancer kills us.
As approximately 83%-87% of diagnosed breast cancers are estrogen-driven/estrogen-positive (ER+), we are now knowledgeable, as well as very much aware, that fat holds onto estrogens, and estrogens hold onto fats, and there are valid and extremely important correlations between fat/fatty acid metabolism and breast cancers. By following this logic, it only holds true that there is also a correlation between carnitine, carnitine’s overall status in the body, and breast cancer. This does not only relate to breast cancer but to other types of cancer that are also driven by estrogens as well.
Carnitine is absolutely essential for the translocation of long-chain fatty acids into the mitochondria, and the relative concentrations of carnitine and acylcarnitines (fatty acids attached to carnitine), in the serum are known to reflect metabolic status. Going back a number of years, a colleague of mine with whom I shared a lab, in conjunction with my major doctoral professor, published a paper in the Journal of the American College of Nutrition1 comparing serum levels of total carnitine fractions in cancer patients, to those of healthy, non-cancer subjects. The prime objective was to record serum carnitine concentrations in both cancer and non-cancer subjects over a period of time in order to obtain these carnitine profiles and to compare differences. What was found was that although most serum carnitine and serum carnitine fraction concentrations were similar in both groups, one of these fractions, the Acid-Soluble Acylcarnitine (ASAC) fraction, did show significantly lower serum concentrations in cancer patients when compared to the non-cancer control subjects. Because the ASAC fraction represents the shorter chain fatty acid-carnitine moiety, this is quite significant. The lower concentrations of the ASAC/shorter chain fatty acid-carnitine fractions in the serum of the cancer patients, (as compared to the normal controls), may be due to either their decreased production, their increased utilization, or even an increased excretion of these acid-soluble acylcarnitines…all part of the “wasting” scenario of cancer.
One fact that should always be considered is that ER+ breast cancers, because their tumors are stimulated by the various estrogens, and the fact that fat and fat tissue hold onto these estrogens, by reducing or utilizing excess fat for energy by L-carnitine supplementation (for instance), would also aid in the removal (via release), of these estrogens from breast fatty tissue and their estrogen receptors when localized fat is broken down and oxidized/utilized for energy. The fact is, that by releasing estrogens into the body, although this action would require a healthy, functional hepatic P-450, drug/toxin-metabolizing system, at least these potentially harmful estrogens would be removed from the vicinity of the breast and from the estrogen receptors of breast tissue and/or other organs and/or tissues.
In a study by Erbas and Aydogdu, et al.2,it was presented that many breast cancer patients are found to have high levels of serum and tissue arginase enzyme and ornithine, which are known as possible “drivers” of specific breast cancers. These investigators examined the protective effects of carnitine and the possibility that it disrupts the arginase-nitric oxide (NO), interaction. Histopathological examination was utilized to determine arginase activity, and ornithine and NO levels were measured in tumor tissues. Both arginase activity and ornithine levels were significantly lowered, while NO levels were significantly elevated in the carnitine-treated groups compared to the controls (i.e., the non-carnitine-treated group). The investigators hypothesized that one possible mechanism of carnitine’s protective role in inhibiting tumor progression may be due to its promotion of NO. If this is the case, this mechanism could decrease the production of tumor-promoting agents while simultaneouesly increasing NO production. Increasing NO production would allow for a better flow of oxygen into tissue, which in itself restricts the promotion and/or thriving of cancer cells, which survive best in poorly oxygenated tissue. In this way, carnitine would exert a significant protective effect on normal, healthy tissue while down-regulating cancer cell promotion and/or its development.
TRAIL (Tumor necrosis factor [TNF]-related apoptosis-inducing ligand), selectively induces cell death in specific tumors yet has little to no toxicity to normal, healthy cells. This is why TRAIL agonists have been considered to be promising anti-cancer agents. Unfortunately, many primary tumors and/or cancer cells do show resistance to TRAIL. Park, S.J. and Park, S.H., et al.3 found that carnitine sensitizes TRAIL-resistant cancer cells to TRAIL itself. These investigators combined the use of carnitine and TRAIL together, and by doing so, were able to show a synergistic inducement of apoptosis (cell death) of cancer cells via activation of the caspase enzyme. In the study, the cancer cells affected were those of lung cancer, colon carcinoma, and breast carcinoma cells. By up-regulating the expression of the pro-apoptotic Bcl-2 family/Bcl-2-associated X protein, known as Bax,by either using the combination of carnitine and TRAIL, or just by utilizing carnitine alone, investigators suggest that these protocols might reverse the resistance of powerful cancer cells using the benign, yet effective, tri-methyl-amino compound, carnitine. The investigators concluded that the combined delivery of carnitine and TRAIL may represent a new therapeutic strategy to treat TRAIL-resistant cancer cells.
In an investigation by Aovida, M., Paulin, R., and Ramotar, D.4, researchers focused on “resistance” that cancer cells have in order to adapt to hostile surroundings and attacks by chemotherapeutic drugs and compounds. One of these compounds is bleomycin. Although bleomycin (an anti-neoplastic agent), is successfully used against many cancers, resistance to this agent remains a persistent limitation in many cancers.
One of these cancers is the MCF-7human breast cancercell which exhibits a striking resistance to this drug. This study demonstrates that modulating the level of L-carnitine transporter hcT2 [agenetically-coded red clover gene-ligand transporter] increases the sensitivity of the MCF-7 breast cancer cells to an anticancer polyamine analogue of bleomycin…thus weakening it (the MCF-1 breast cancer cell), and making it more susceptible to the drug’s anti-neoplastic effects.
Although invasive forms of breast cancer are treated in various ways, one of the cornerstones of treatment is via the use of a highly toxic class of agents called anthracyclines. Epirubicin (a stereoisomer of the anthracyline antibiotic/anti-metabolite, doxorubicin), is one of these drugs that is commonly used against invasive breast cancer. While epirubicin therapy is quite effective against breast cancer, this drug, similar to any anthracycline, has an eventful array of toxicities; and in particular, epirubicin is extremely toxic to the tissues of the heart and the cardiac muscles. Many patients who follow an epirubicin protocol do present severe cardiomyopathy.
Using what we know about L-carnitine and its cardio-protective properties 5-7, and the fact that L-carnitine is an essential cofactor for proper oxidative metabolism, (especially necessary and required for proper heart health and function), investigators8 wanted to hypothesize if the supplementation of carnitine to breast cancer patients being treated with epirubicin, could be used to reduce the development of cardiac toxicity in these treated patients.
Delaney, C.E., Hopkins, S.P., and Addison, C.L.8 tested whether the addition of L-carnitine altered the tumor cytotoxic effects of epirubicin using a number of in vitro cell viability assays in different breast cancer cell lines, including, BT549, MDA-MB-435, NC-ADR-RES, MCF-7, and T47D. It was found that the addition of L-carnitine had no effect on the ability of epirubicin to kill nor inhibit the variety of these breast cancer cell lines, and no differences in the induction of apoptosis by the drug were observed. In addition, all cell lines which were examined expressed proteins required for carnitine uptake and use. Thus, the investigators suggest that from the data collected, the co-administration of supplemental carnitine, when given along with epirubicin, does not impair the ability of the drug to kill cancer cells. The results do suggest that L-carnitine supplementation in patients undergoing epirubicin treatment is safe, and that carnitine could be safely used to possibly reduce the associated cardiotoxicities of the drug without jeopardizing the efficacy of the chemotherapeutic regimen.
Although carnitine has many recorded benefits for those who suffer from various sicknesses and organic conditions (breast cancer being just one example), patients suffering from a serious diagnosis should always clear their use of carnitine, as well as with all supplements (just as they would with any medications), with their physician. If cancer has been diagnosed, this is an even more important rule to follow. There are 2 reasons for this:
First, if carnitine is indeed inducing fat catabolism for the purposes of using long-chain fatty acids for energy, if estrogens, xenoestrogens, and the wide variety of fat-soluble toxins are released from the targeted fatty tissue, these “poisons” would be released in the body and could situate themselves in other fat-storage areas in the body. If the liver and kidney and other P450-drug-metabolizing organs and tissues are not functioning well enough to metabolize and excrete these poisons (which is the case with many cancer patients who are already metabolically compromised), then these actions could cause secondary problems and/or issues in other areas of the body.
Second, carnitine tastes just awful. In order to mask the taste of carnitine, unless it is taken in pill or tablet form, where it is poorly absorbed, and it is used as a powder or a liquid, many companies may use certain additives (such as sugar and/or preservatives), that you may not realize are in the mix. (Sugar would be poison for someone with cancer, and certain preservatives could add a lot of stress on an already compromised body.) The carnitine that is used in industrial or academic research normally is of pharmaceutical grade and comes directly from pharmaceutical companies such as Sigma Tau (Italy), for instance, that hasn’t been altered in any way.
The bottom line; if an individual has cancer and wants to use carnitine, he or she should always carefully read and investigate all of the ingredients in the carnitine supplement, while also allowing for the opinion of his or her physician, oncologist, or Registered dietician about this. The carnitine must be of the L-form (i.e., L-carnitine), and one should never use a racemic [50:50] mixture form (i.e., D,L-carnitine).
The reason for the statement above; D-carnitine is physiologically inactive and is not recognized by the body, a D,L -carnitine mixture would be only 50% active…and 100% activity is desired, especially when the body is compromised due to any condition or disease. Also, D-carnitine can actually work against the positive effects of L-carnitine, by either blocking its effectiveness or actually doing harm to the body in specific cases.
1.Sachan, D.S. and Dodson, W.L. (1987)The serum carnitine status of cancer patients. J. Am. Coll. Nutr., 6, 145.
2.Erbas, H. and Aydogdu, N., et al. (2007)Protective role of carnitine in breast cancer via decreasing arginase activity and increasing nitric oxide. Cell Biol. Int., 31, 1414.
3.Park, S.J. and Park, S.H., et al. (2012) Carnitine sensitizes TRAIL-resistant cancer cells to TRAIL-induced apoptotic cell death through the up-regulation of BAX. Biochem. Biophys. Res. Commun., 428, 185.
4. Aovida, M., Poulin, R., and Ramotar, D. (2010)The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5. J. Biol. Chem., 285, 6275.
5.Pauly, D.F. and Pepine, C.J. (2003) The role of carnitine in myocardial dysfunction. Am. J. Kidney Dis., 41, S35.
6. Najafi, M. and Javidnia, A., et al. (2010) Pharmacological preconditioning with L-carnitine: relevance to myocardial hemodynamic function and glycogen and lactate content. Pak. J. Pharm. Sci., 23, 250.
7. Ilias, I. and Manoli, I., et al., (2004) L-carnitine and acetyl-L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy. Mitochondrion, 4, 163.
8. Delaney, C.E., Hopkins, S.P., and Addison, C.L. ( 2007)Supplementation with l-carnitine does not reduce the efficacy of epirubicin treatment in breast cancer cells. Cancer Lett., 252, 195.
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