An interesting fishing expedition

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Nov 11, 2008 - Burns CP, Halabi S, Clamon G, Kaplan E, Hohl RJ, Atkins JN, et al. ... Cha MC, Meckling KA, Stewart C. Dietary Docosahexaenoic acid levels ...
[Cancer Biology & Therapy 8:4, 338-339; 15 February 2009]; ©2009 Landes Bioscience

Commentary

An interesting fishing expedition Peter J. Quesenberry* and James N. Butera Rhode Island Hospital; Hematology/Oncology; Providence, RI USA

Key words: docosahexanoic acid, leukemia, apoptosis, stem cells, clinical trials

Fish oil and its major component, Docosahexaenoic acid, has been purported to be beneficial for the treatment of a variety of illnesses including coronary artery disease, hyperlipidemia, rheumatoid arthritis, Alzheimer disease and macular degeneration.1-5 With regard to cancer, most of the clinical literature on fish oil has been on its purported ability to ameliorate the symptoms of cancer cachexia, produce normalizing effects on abnormal rectal proliferation patterns associated with increased colon cancer risk, protect against breast cancer and ameliorate the toxicities of chemotherapy.6-9 In this issue of Cancer Biology & Therapy, Yamagami and colleagues have studied the effects of docosahexanoic acid on the KG1a leukemic cell line.10 This work builds on previous work looking at the apoptotic effects of Docosahexanoic acid on human leukemia cell lines.11 Previous work has shown that Docosahexanoic acid enhances the toxic effect of imatinib on Bcr-Abl expressing human leukemia cell lines as well as enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant human leukemia cells.12,13 Another study has correlated dietary Docosahexaenoic acid to improved survival in leukemic mice receiving Cytarabine.14 However, despite the ten years of in vitro and pre-clinical research for fish oils as a possible weapon against leukemia, there have been no published clinical trials examining its role for leukemic patients. The lack of clinical trials in this area may be due to its perception in the medical literature as a panacea to many medical ills, therefore making it hard to accept that it may have specific efficacy in leukemia. One may ask, “How can it be good for heart disease, lipids, cognitive impairments, macular degeneration, rheumatoid arthritis and leukemia?” Nonetheless, these authors (as with others in the past) do present compelling data that Docosahexaenoic acid may exhibit antileukemic properties in vitro. Certainly, the past successes of agents such as all-trans-retinoic acid in acute promyelocytic leukemia and thalidomide in multiple myeloma can teach us that although an agent may be available for decades, it may only be when it is tried *Correspondence to: Peter J. Quesenberry; Rhode Island Hospital; Hematology/ Oncology; 593 Eddy Street; George 3, Room 302; Providence, RI 02903 USA; Tel.: 401.444.4830; Fax: 401.444.4184; Email: [email protected] Submitted: 11/11/08; Accepted: 01/12/09 Previously published online as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cbt/article/7832 Commentary to: Yamagami T, Porada CD, Pardidi RS, Zanjani ED, Almeida-Porada G. Docosahexaneoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell line. Cancer Biol Ther 2009; This issue. 338

in clinical trials can the real potential of its anti-neoplastic effects be seen. Furthermore, we have witnessed impressive anti-neoplastic efficacy from natural sources in the past. The success of paclitaxel, which comes from the Pacific yew, Taxus brevifolia Nutt, a small understory tree from the Pacific Northwest forests, is one example of this. There are, however, caveats to the Yamagami paper. They mention the importance of studying leukemic cells that are resistant to chemotherapy because these cells may represent leukemic stem cells.15 To date, there is no compelling evidence that this cell line represents a stem cell line. In fact, the existence of rare stem cells in acute leukemia has been questioned by work employing syngeneic mouse cells.16 It has been postulated that the xenogeneic setting of human cells in immunodeficient mice detects only cells that can survive this very adverse environment and does not assay a leukemic stem cell. This being said, it is clear that leukemic stem cells do exist in the disease chronic myelocytic leukemia.17 The relapses of CML after stopping Gleevec in patients previously in complete remission, is strong evidence of the existence of a rare Gleevec resistant CML stem cell. Therefore, further characterization of this line will be important. Well-designed clinical trials to test the effects of Docosahexanoic acid in AML are eagerly awaited. References 1. Saldeen TG, Mehta JL. Dietary modulations in the prevention of coronary artery disease: A special emphasis on vitamins and fish oil. Curr Opin Cardiol 2002; 17:559-67. 2. Damsgaard CT, Frokiaer H, Andersen AD, Lauritzen L. Fish oil in combination with high or low intakes of linoleic acid lowers plasma triacylglycerols but does not affect other cardiovascular risk markers in healthy men. J Nutr 2008; 138:1061-6. 3. Galarraga B, Ho M, Youssef HM, Hill A, McMahon H, Hall C, et al. Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47:665-9. 4. Hooijmans CR, Kiliaan AJ. Fatty acids, lipid metabolism and Alzheimer pathology. Dur J Pharmacol 2008; 585:176-96. 5. Augood C, Chakravarthy U, Young I, Vioque J, de Jong PT, Bentham G, et al. Oily fish consumption, dietary Docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr 2008; 88:398-406. 6. Burns CP, Halabi S, Clamon G, Kaplan E, Hohl RJ, Atkins JN, et al. Phase II study of highdose fish oil capsules for patients with cancer-related cachexia. Cancer 2004; 101:370-8. 7. Anti M, Armelao F, Marra G, Percesepe A, Bartoli GM, Palozza P, et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 1994; 107:1709-18. 8. Engeset D, Alsaker E, Lund E, Welch A, Khaw KT, Clavel-Chapelon F, et al. Fish consumption and breast cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 2006; 119:175-82. 9. Cha MC, Lin A, Meckling KA. Low dose Docosahexaenoic acid protects normal colonic epithelial cells from araC toxicity. BMC Pharmacol 2005; 5:7. 10. Yamagami T, Porada CD, Pardini RS, Zanjani ED, Almeida-Porada G. Docosahexanoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell line. Cancer Biol Ther 2009; 8:331-7. 11. Chiu LC, Wong EY, Ooi VE. Docosahexaenoic acid modulates different genes in cell cycle and apoptosis to control growth of human leukemia HL-60 cells. Int J Oncol 2004; 25:737-44. 12. de Lima TM, Amarante-Mendes GP, Curi R. Docosahexaenoic acid enhances the toxic effect of imatinib on Bcr-Abl expressing HL-60 cells. Toxicol In Vitro 2007; 21:1678-85.

Cancer Biology & Therapy

2009; Vol. 8 Issue 4

Fish oil and leukemia

13. Sturlan S, Baumgartner M, Roth E, Bachleitner-Hofmann T. Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells. Blood 2003; 101:4990-7. 14. Cha MC, Meckling KA, Stewart C. Dietary Docosahexaenoic acid levels influence the outcome of arabinosylcytosine chemotherapy in L1210 leukemic mice. Nutr Cancer 2002; 44:176-81. 15. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367:645-8. 16. Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A. Tumor growth need not be driven by rare cancer stem cells. Science 2007; 317:337. 17. Kavalerchik E, Goff D, Jamieson CH. Chronic myeloid leukemia stem cells. J Clin Oncol 2008; 26:2911-5.

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