Saturated fatty acids of general formula CH3(CH2)
Abstract
Recent research supports the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) on inhibiting tumour development. Long‐chain fatty acids modulate the tumour cell response to chemotherapeutic drugs. Investigators recently claimed high dietary intake of omega‐6 polyunsaturated fatty acids such as linoleic acid especially in association with a low intake of omega‐3 polyunsaturated fatty acids such as docosahexaenoic acid to increase risks for cancers of the breast, colon and possibly prostate. In addition to these facts, a number of investigations have demonstrated that a modified fatty acid analogues are promising molecules in cancer prevention and have potential in the treatment of cancer. Although billions of dollars have been spent on research and development on anticancer drugs, the disease remains uncontrolled. It is expected that anticancer agents preferentially kill tumour cells without causing adverse effects on normal cells. But this is rarely achieved with the existing cancer therapy. Hence, polyunsaturated fatty acids have come under the category of nutraceuticals/functional foods; their exploration in the treatment of cancer may be considered as safe. This chapter describes the effects of long‐chain fatty acids and their analogues in cancer chemotherapy.
Keywords
- fatty acids
- cancer
- PUFA
- fatty acid synthase
- omega‐3
1. Introduction to fatty acids
Plants, animals and microbes generally contain even number of carbon atoms in straight chains, with a carboxylic group at one end and double bonds with
Fatty acids may be monounsaturated, polyunsaturated or saturated (Figure 1). They help in moving oxygen through the blood stream to all parts of the body, aid cell membrane development and strengthen the organs and tissue. They also help in healthy skin and prevent early ageing and more importantly help rid the arteries of cholesterol build‐up.
2. Types of fatty acids
2.1. Saturated fatty acids
Saturated fatty acids are straight‐chain compounds with 14, 16 and 18 carbon atoms. The most abundant saturated fatty acids found in animal and plant tissues are esterified with odd‐ and even‐numbered homologues with 2–36 carbon atoms. A list of common saturated fatty acids together with their trivial names and shorthand designations is given in Table 1.
S. no. | Systematic name | Shorthand designation | Trivial name |
---|---|---|---|
1. | Ethanoic | 2:0 | Acetic |
2. | Butanoic | 4:0 | Butyric |
3. | Hexanoic | 6:0 | Caproic |
4. | Octanoic | 8:0 | Caprylic |
5. | Nonanoic | 9:0 | Pelargonic |
6. | Decanoic | 10:0 | Capric |
7. | Undecanoic | 11:0 | – |
8. | Dodecanoic | 12:0 | Lauric |
9. | Tridecanoic | 13:0 | – |
10. | Tetradecanoic | 14:0 | Myristic |
11. | Pentadecanoic | 15:0 | Myristic |
12. | Hexadecanoic | 16:0 | Palmitic |
13. | Heptadecanoic | 17:0 | Margaric |
14. | Octadecanoic | 18:0 | Stearic |
15. | Nonadecanoic | 19:0 | Margaric |
16. | Arachidic | 20:0 | Eicosanoic |
17. | Heneicosanoic | 21:0 | – |
18. | Docosanoic | 22:0 | Behenic |
19. | Tetracosanoic | 24:0 | Lignoceric |
2.2. Monoenoic fatty acids
Monoenoic fatty acids are straight‐chain fatty acids containing 10–30 carbon atoms with one
S. no. | Systematic name | Shorthand designation | Trivial name |
---|---|---|---|
1. | 14:1(n‐5) | Myristoleic | |
2. | 16:1(n‐7) | Palmitoleic | |
3. | |||
18:1(n‐12) | Petraselenic | ||
4. | 18:1(n‐9) | Oleic | |
5. | 18:1(n‐7) | ||
6. | Elaidic | ||
7. | 20:1(n‐11) | Gadoleic | |
8. | 18:1(n‐9) | Gondic | |
9. | 22:1(n‐9) | Erucic | |
10. | 24:1(n‐9) | Nervonic |
2.3. Polyunsaturated fatty acids
Polyunsaturated fatty acids (PUFAs) are fatty acids which contain multiple double bonds and are subdivided into families according to their derivation from specific biosynthetic precursors. In each instance, the families contain between two and six
S. no. | Systematic name | Shorthand designation | Trivial name |
---|---|---|---|
1. | 9,12‐Octadecadienoic* | 18:2(n‐6) | Linoleic |
2. | 6,9,12‐Octadecatrienoic | 18:3(n‐6) | γ‐Linolenic |
3. | 8,11,14‐Eicosatrienoic | 18:3(n‐6) | Homo‐γ‐linolenic |
4. | 5,8,11,14‐Eicosatetraenoic | 20:4(n‐6) | Arachidonic |
5. | 4,7,10,13,16‐Eicosapentaenoic | 20:5(n‐6) | – |
6. | 9,12,15‐Octadecatrienoic | 18:3(n‐6) | α‐Linolenic |
7. | 5,8,11,14,17‐Eicosapentaenoic | 20:5(n‐3) | EPA |
8. | 7,10,13,16,19‐Docosapentaenoic | 22:5(n‐3) | – |
9. | 4,7,10,13,16,19‐Docosahexaenoic | 22:5(n‐3) | DHA |
10. | 5,8,11‐Eicosatrienoic | 20:3(n‐9) | Mead’s acid |
2.4. Branched‐chain and cyclopropane fatty acids
Branched‐chain fatty acids, which occur widely in nature, are present as minor components except in bacteria, where they appear to replace unsaturated fatty acids functionally. The branch consists of a single methyl group, either on the penultimate (
2.5. Oxygenated and cyclic fatty acids
A large number of hydroperoxy, hydroxyl and epoxy fatty acids (eicosanoids) are formed enzymatically as intermediates in the biosynthesis of prostanoids. A large number of hydroxy fatty acids occur in seed oils, and the best known of these is ricinoleic acid which is the principle constituent of castor oil. Polyhydroxy fatty acids are present in plant cutins, shellacs and many seed oils.
2.6. Omega‐3 and omega‐6 fatty acids
The biological fatty acids are of different lengths, the last position is labelled as
Although the International panel of lipid experts says the ideal ratio of
3. Polyunsaturated fatty acids as anticancer agents
Yonesawa and co‐workers carried out the inhibitory effect of conjugated eicosapentaenoic acid (cEPA) on mammalian DNA polymerase and topoisomerase activities and human cell proliferation. They found that the inhibitory effect of cEPA was stronger than that of the non‐conjugated EPA and suggested the therapeutic potential of cEPA as a leading anticancer compound that poisons mammalian DNA polymerase (POLS) [7]. The work carried by
The author and her research group isolated methyl gamma linolenate (
S. no. | Compound | Concentration (µM) | % growth inhibition | CTC50 |
---|---|---|---|---|
1. | 3.333 | 97.45 | 0.468 | |
2. | 1.666 | 86.39 | ||
3. | 0.833 | 72.38 | ||
4. | 0.416 | 48.45 | ||
5. | 3.333 | 98.65 | 0.442 | |
6. | 1.666 | 88.41 | ||
7. | 0.833 | 75.25 | ||
8. | 0.416 | 49.05 |
4. Polyunsaturated fatty acids as adjunct to chemotherapeutic agents
Kong and co‐workers found out that gamma linolenic acid modulates the response of multidrug‐resistant K562 leukaemic cells to anticancer drugs. The study also revealed that GLA could modulate the response to anticancer drugs in P‐gp overexpressing multidrug‐resistant cells, which could be due to decrease P‐gp expression [15]. In another study, Julie and co‐workers reported that alpha linolenic acid and docosahexaenoic acid alone combined with trastuzumab reduced HER2 overexpressing breast cancer cell growth but differentially regulated HER2‐signalling pathways. Their finding is different in classic mechanisms whereby n‐3 PUFAs exert their effect in breast cancer. The results strongly suggest that DHA reduces growth factor receptor signalling as indicated by reductions in the phosphorylation of AKT and MAPK while the opposite effect is seen for the plant‐based n‐3 PUFA ALA [16]. Effenberger and co‐workers synthesized novel N‐acylhydrazones of doxorubicin which were derived from saturated, unsaturated and methyl or bornyl terminated fatty acids. The mode of cytotoxic action of the hydrazones was largely apoptotic. They led to a distinct long‐term decrease of bcl‐2 MRNA expression, the precise apoptotic mechanism and the involvement of caspases varied for the individual cell lines and test compounds. The apoptosis of 518A2 melanoma cells treated with some compounds was characterized by an early onset of initiator caspase‐9 activity. By contrast, apoptosis elicited in 518A2 or in HL‐60 cells by remaining compounds was accompanied by high‐initiator caspase‐8 activity. The genuine slump of the bcl‐2 mRNA expression may be the reason for the observed quick and steep hike of the ratio of bax mRNA to bcl‐2 mRNA in 518A2 cells. Apoptosis induced by doxorubicin
Piyali
5. Fatty acid analogues as anticancer agents
A number of investigations have demonstrated that a variety of modified fatty acid analogues are promising molecules in cancer prevention and have potential in the treatment of cancer. Bhupender
They also synthesized fatty acyl ester derivatives (
Zhang Chun‐hong and co‐workers synthesized new panaxadiol fatty acid esters (
Earlier, the author of the present chapter has reported some novel fatty acid heterocyclic conjugates and their anticancer evaluation on human lung carcinoma cell lines [23, 24]. The compounds have shown comparable cytotoxicity towards human lung carcinoma cell lines. The compound (
6. Fatty acid synthase as a potential target in cancer
Human fatty acid synthase (HFAS) is a multifunctional enzyme that is essential for the endogenous synthesis of long‐chain fatty acid from its precursor acetyl Co‐A and malonyl Co‐A (Figure 4). Blocking HFAS activity causes cytotoxicity [25]. The unique carboxyl terminal thioesterase (TE) domain of fatty acid chain plays a critical role in regulating the chain length of fatty acid releases. Also, the up‐regulation of HFAS in a variety of cancer makes the thio‐esterase domain a candidate target for therapeutic treatment [26]. It was evident from the literature that the long alkyl/alkenes tail of the fatty acids can bind into the long groove tunnel site of thio‐esterase domain of FAS which may be one of the factors of anticancer activities of fatty acids [27].
Employing these strategies, the author and her research group carried out the
Babak Oskouian and co‐workers reported the overexpression of fatty acid synthase in SKBR3 breast cancer cell line and. The objective of this study was to use a breast cancer‐derived cell line, SKBR3, as a model to define the underlying mechanism for overexpression of FAS in cancer cells [31]. Silva
7. Concluding remarks
As part of a conclusion to our discussion, the various studies have shown that fatty acids not only augment the tumouricidal action of anticancer drugs but also enhance the uptake of anticancer drugs leading to an increase in the intracellular concentration of the anticancer drugs. The omega‐3 fatty acids have become adjutants to chemotherapeutic agents. Although the production of the above‐said fatty acids is a big challenge, a possibility would be gradually implementing the production of these fatty acids in clinical use. Such novel uses of fatty acids in cancer therapy would provide the lipid field with a new avenue to impact public health.
References
- 1.
Gunstone FD. The Lipid Handbook. London: Chapman and Hall; 1986 - 2.
Robinson PG. Common names and abbreviated formulae for fatty acids. Journal of Lipid Research. 1982; 23 :1251-1253 - 3.
Garton GA. Aspects of the chemistry and biochemistry of branched‐chain fatty acids. Chemistry and Industry (London). 1985:295-300 - 4.
Lough AK. The chemistry and biochemistry of phytanic, pristanic and related acids. Progress in the Chemistry of Fats and Other Lipids. 1973; 14 :1-48 - 5.
Simopoulos AP. The importance of the ratio of omega‐6/omega‐3 essential fatty acids. Biomedicine & Pharmacotherapy. 2002; 56(8) :365-379 - 6.
William WC. Gas Chromatography and Lipids. Bridgwater, Somerset; The Oily Press; 1989. pp. 9-10 - 7.
Yonezawa Y, Hada T, Uryu K, Tsuzuki T, Eitsuka T, Miyazawa T. Inhibitory effect of conjugated eicosapentaenoic acid on mammalian DNA polymerase and topoisomerase activities and human cancer cell proliferation. Biochemical Pharmacology. 2005; 70 :453-460 - 8.
Unduri ND. Tumoricidal and anti angiogenic actions of gamma linolenic acid and its derivatives. Current Pharmaceutical Biotechnology. 2006; 7 :457-466 - 9.
Paul DT, Thomas ER, Alicja W. Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone‐related cancers: A review of the epidemiologic evidence. The American Journal of Clinical Nutrition. 2003; 77 :532-543 - 10.
Carol JF, Bruce FK, Stephen DH. Omega‐3‐fatty acids for breast cancer prevention and survivorship. Breast Cancer. 2015; 17 :62 - 11.
Helmut B, Jagadeesan N, Robert WO. Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: Emerging evidence for their role as risk modifiers. Carcinogenesis. 1999; 20(12) :2209-2218 - 12.
Susanna CL, Maria K, Sundberg M, Alicja W. Dietary long chain n‐3 fatty acids for the prevention of cancer; a review of potential mechanisms. The American Journal of Clinical Nutrition. 2004; 79 :935-945 - 13.
Jubie S, Dhanabal SP, Chaitanya MVNL. Isolation of methyl gamma linolenate from Spirulina platensis using flash chromatography and its apoptosis inducing effect. BMC Complementary and Alternative Medicine. 2015;15 :263 - 14.
Ren W, Qiao Z, Wang H, Zhu L, Zhang L. Flavanoids: Promising anticancer agents. Medical Research Reviews. 2003; 23 :519-534 - 15.
Kong X, Ge H, Chen L, Liu Z, Yin Z, Li P. Gamma linolenic acid modulates the response of multidrug resistant K562 leukemic cells to anticancer drugs. Toxicology In Vitro . 2009;23 :634-639 - 16.
Julie KM, Suskpreet K, Shikhil K, Ashleigh KAW, Lilan UT. α‐Linolenic acid and docosahexaenoic acid, alone and combined with trastuzumab reduce HER2‐overexpressing breast cancer cell growth but differentially regulate HER2 signalling pathways. Lipids in Health and Diseases. 2015; 14 :91 - 17.
Effengberger K, Breyer S, Schobert R. Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones. European Journal of Medicinal Chemistry. 2010; 489 :1947-1954 - 18.
Piyali D, Anu S, Rama M. N‐Terminal acylation of somatostatin analog with long chain fatty acids enhances its stability and antiproliferative activity in human breast carcinoma cells. Biological and Pharmaceutical Bulletin. 2002; 28(1) :29-36 - 19.
Bhupender SC, Nicole SJ, Deendayal M, Anil Kumar, Keykavous P. Fatty acyl amide derivatives of doxorubicin: Synthesis and in vitro anticancer activities. European Journal of Medicinal Chemistry. 2011;46 :2037-2042 - 20.
Bhupender SC, Deendayal M, Keykavous P. Synthesis and evaluation of fatty acyl ester derivatives of cytarabine as anti‐leukemia agents. European Journal of Medicinal Chemistry. 2010; 45 :4601-4608 - 21.
Liu B, Cui C, Duan W, Zhao M, Feng S, Wang L, Liu H, Cui C. Synthesis and evaluation of antitumour activities of N4 fatty acyl amino acid derivatives of 1‐β‐arabinofuranosylcytosine. European Journal of Medicinal Chemistry. 2009; 44 :3596-3600 - 22.
Zhang CH, Li XG, GaoYG, Zhang LX, FU XQ. Synthesis and primary research on antitumor activity of three new panaxadiol fatty acid esters. Chemical Research in Chinese Universities. 2007; 23(2) :176-182 - 23.
Jubie S, Pawan Kumar Y, Chandrasekar MJN. Novel fatty acid analogues as fatty acid synthase‐thio esterase domain inhibitors; Synthesis and their cytotoxicity screening. Letters in Drug Design and Discovery. 2015; 12 :495-499 - 24.
Jubie S, Dhanabal SP, Afzal Azam M, Muruganandham N, Kalirajan R, Elango K. Synthesis and characterization of some novel fatty acid analogues: A preliminary investigation against human lung carcinoma cell line. Lipids in Health and Diseases. 2013; 12 :45 - 25.
Teresa P, Helena A, Sílvia C, Glòria O, Carlos T, Sílvia OG, et al. A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti‐HER2 drug‐resistant cell lines. Breast Cancer Research. 2011; 13 :R131 - 26.
Kuhajda, FP, Pizer ES, Li JN, Mani, NS, Frehywot GL, Townsend CA. Synthesis and antitumour activity of an inhibitor of fatty acid synthase. Proceedings of National Academic Sciences of the United States of America. 2000; 97(7) :3450-3454 - 27.
Chakravarty B, Gu ZW, Chairala SS, Wakil SJ, Quiocho FA. Human fatty acid synthase: Structure and substrate selectivity of the thioesterase domain. Proceedings of National Academic Sciences of the United States of America. 2004; 101 :15567-15572 - 28.
Kuhajda FP, Piantadosi S, Pasternack GR. Haptoglobin‐related protein (Hpr) epitopes in breast cancer as a predictor of recurrence of the disease. New England Journal of Medicine. 1989; 321: 636-641 - 29.
Kuhajda FP, Katumuluwa AI, Pasternack GI. Expression of haptoglobin related protein and its potential role as a tumor antigen. Proceedings of National Academic Science USA. 1989; 86 :1188-1192 - 30.
Nardini M, Dijkstra BW. α/β hydrolase fold enzymes: The family keeps growing. Current Opinion in Structural Biology. 1999; 9(6) :732-737 - 31.
Babak O. Overexpression of fatty acid synthase in SKBR3 breast cancer cell line is mediated via a transcriptional mechanism. Cancer Letters. 2000; 149 :43-51 - 32.
Sabrina DS, Michelle A, Ines NN, Ricardo DC, Fabio AA, Marcio AL, Luiz PK, Edgard G. Expression of fatty acid synthase, ErbB2 and Ki‐67 in head and neck squamous cell carcinoma. A clinicopathological study. Oral Oncology. 2004; 40 :688-696 - 33.
Michelle A, Sabrina DS Karina GZ, Ricardo DC, Jacks J, Massimo L, Edgard G. Fatty acid synthase is required for the proliferation of human oral squamous carcinoma cells. Oral Oncology. 2004; 40 :728-735