Academic Editor: Bashir A. Lwaleed, Faculty of Health Sciences, University of Southampton.
Checked for plagiarism: Yes
Review by: Single-blind
Copyright © 2014 Spiros A. Vlahopoulos.
The authors have declared that no competing interests exist.
A recent clinical trial for pediatric embryonal brain tumors reported encouraging results, with a treatment scheme that included peroxisome proliferator-activated receptor-α (PPARα) agonist fenofibrate 1. The treatment scheme was aimed at inhibiting neovascularization; however, the drugs used can inhibit cancer cell growth by a number of mechanisms. In a different treatment scheme, aimed to treat a variety of recurrent or progressive tumors, fenofibrate could not demonstrate similarly encouraging effects 2.Under which conditions can fenofibrate be effective?
In basic and clinical research, PPAR agonists are generally used to inhibit angiogenesis 1, 2, 3. However, it has been revealed that they can stimulate angiogenesis as well, using as models human cultured endothelial cells and mouse cornea 4. It could be argued that cell type and microenvironment determine effects on angiogenesis, and can be determined by the cell and host composition of the preclinical study model.
Downstream targets of PPAR agonists can have multiple effects on gene expression and cell physiology: The subject of PPAR ligands as anticancer drugs has been reviewed recently. Grabacka et al., note that PPARα activation can engage molecular interplay among SIRT1, AMPK, and PGC-1α 5 which could explain, at least in part, the encouraging results of the Peyrl et al., study (more on this topic in 6). In cultured cervical cancer cells, however, fenofibrate can induce mRNA for PPARα, PPARγ and superoxide dismutase 1, with tendency to decrease radiation sensitivity 7. In different types of gastrointestinal cancer, PPAR activity above or below normal can affect tumor growth 8. High PPAR activity can kill cancer cells that are unable to utilize fatty acids as a source of energy, or that depend on signals mediated by transcription factors NF-kB or STAT3; on the other hand PPAR activity can support growth of cancer cells that are deficient in tumor suppressors such as APC, or cancer cells that derive energy from oxidation of fatty acids 8.
Interestingly, in a recent mechanistic study on chronic lymphocytic leukemia (CLL), inhibitors of PPARα and fatty acid oxidation enzymes increased glucocorticoid-mediated killing of CLL cells in culture. The study authors noted a similar effect on mouse CLL xenografts, where immune-deficient mice could be rescued by combination of GCs and PPARα inhibition 9. CLL cells may use fatty acids as a source of energy, because they express lipoprotein lipase: palmitate oxidation rates in circulating CLL cells can be similar to normal fat-burning cells such as muscle 10. Transgenic expression of PPARα in the cell line Daudi, increased both expression of immunosuppressive factors interleukin (IL)10 and phospho-STAT3 and resistance to metabolic and cytotoxic stress; in contrast, PPARα antagonist MK886 killed circulating CLL cells directly, caused proliferating CLL cells to enter an immunogenic death pathway and cleared CLL xenografts from immunodeficient mice. 10.
Lipoprotein lipase is highly expressed in bone marrow mesenchymal stem cells of acute myeloid leukemia patients, making those marrow cells prone to adipogenic differentiation, and thereby contributing to alteration of the bone marrow as a niche 11.
It is clear that balance of metabolic function is critical to the function of bone marrow as a niche for hematopoetic cells: in normal hematopoietic stem cells, regulation of mitochondrial fatty acid oxidation is essential for their function. Inhibition of fatty acid oxidation results in symmetric commitment 12.
Inflammatory signals are an important parameter of PPAR effects on cancer development. In mouse liver, deletion of PPARα aggravates lipopolysaccharide -induced hepatic injury through activating transcription factors STAT1 and NF-κB-p65 and increasing levels of pro-inflammatory cytokines. The activities of key anti-oxidant enzymes and mitochondrial complexes decrease while lipid peroxidation and protein nitration levels increase 13. Similarly, inhibition of PPARγ in mouse myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis14.
The ability of nuclear receptors to interfere with specific aspects of inflammatory signals is crucial to the effects of PPAR agonists. Against Mantle cell lymphoma (MCL), fenofibrate was shown to inhibit activity of the transcription factor NF-kB, killing the malignant cells 15. It must be noted that NF-kB has a wide range of effects on nuclear receptors 16, 17, and that nuclear receptors have a broader role in cancer cells than the one anticipated by their function in classical endocrinology of healthy tissue 18, 17.
Breast cancer cells survive due to enhancement of NF-kB activity by glucocorticoids 19. NF-kB may also be activated by PPARα in breast cancer initiating cells 20. Activation of NF-kB facilitates plasmacytoma cell resistance to glucocorticoids and to inhibitors of Janus kinases, and enables the cells to grow in the absence of Interleukin-6 21. In acute leukemia activation of NF-kB was associated with glucocorticoid treatment failure in children 22, and chemotherapy failure in adults 23. In cell culture, persistent activation of NF-kB could protect Acute Myeloid Leukemia cells from proteasome inhibitor bortezomib 24.
The importance of regulation of inflammatory mechanisms by nuclear receptors and their ligands is also evident in comparison of the effects of fibrates and glucocorticoids between rodents and primates. Fibrates have partly different effects in the liver of a primate (cynomolgus monkey) in comparison to rodents (rats and mice). When mice and rats are given PPARα agonists, they show hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis; these effects are accompanied by a higher expression of inflammatory genes in rodent liver, in comparison to monkeys 25. The inflammatory effects in mice, however, can be modulated by glucocorticoids, as there appears to be a synergy of PPAR and GR against inflammatory signals 26, 27: PPARα blocks glucocorticoid receptor-mediated transactivation but cooperates with liganded glucocorticoid receptor for transrepression on NF-kB 28. As result, in mice with hyperinsulinemia through high-fat diet, activation of PPARα limits GC-induced Glc intolerance 28.
A synergy of nuclear receptors against inflammatory mediators can have importance for leukemic cells that are resistant to glucocorticoids 29; such cells can be killed in vitro by proteasome in inhibitor with a gene expression signature enriched for the STAT3 signal pathway 30. The clinically permitted exposure, however, to the proteasome inhibitor, is rather low 31, and bone marrow cells may modulate STAT3 signals 32. Interestingly, chronic treatment with fenofibrate inhibits STAT3 activation, and prevents the IL-6-induced gene expression in wild-type but not in PPARα-deficient mice 33. Tissue-specific modulators of PPARα could be therefore effective, to interfere with selected targets of the glucocorticoids in cancer cells in vivo 34. For types of tumor cells that cannot integrate fatty acid oxidation in their metabolism, even fenofibrate should be studied as part of the antineoplastic drug combination, including however preferably assays not only on the malignant cells, but also on the cells that form their niche. As described, the molecular endpoint targets of PPAR pathways are useful variables in the analysis of drug interactions at the level of cell culture. In conclusion, PPAR activators like fenofibrate have a high potential as anticancer drugs; and due to interference with glucocorticoid signals, are particularly interesting in leukemia. Fenofibrate is capable, however, for negative effects in antineoplastic treatment, especially on cancer cell types that utilize fatty acid oxidation as an energy source, and as a pathway for resistance to drugs. Advance in molecular study of homeostatic mechanisms, with particular attention to aspects specific for the human organism 35, will enable progress in design of combination schemes for this type of PPAR agonists.
- 1Peyrl A, Chocholous M, Kieran M W, Azizi A A, Prucker C et al.Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. , Pediatr Blood Cancer 2012, 511-7.
- 2Robison N J, Campigotto F, Chi S N, Manley P E, Turner C D et al. (2013) A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer.
- 3Aljada A, O’Connor L, Fu Y-Y, Mousa S A.PPAR gamma ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. , Angiogenesis 2008, 361-7.
- 4Biscetti F, Gaetani E, Flex A, Aprahamian T, Hopkins T et al.Selective activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPAR gamma induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism. , Diabetes 2008, 1394-404.
- 5Grabacka M, Pierzchalska M, Reiss K.Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitochondrial metabolism. , Curr Pharm Biotechnol 2013, 342-56.
- 6Revollo J R, Li X.The ways and means that fine tune Sirt1 activity. , Trends Biochem Sci 2013, 160-7.
- 7Liu X, Jang S S, An Z, Song H, Kim W-D et al.Fenofibrate decreases radiation sensitivity via peroxisome proliferator-activated receptor α-mediated superoxide dismutase induction in HeLa cells. , Radiat Oncol J 2012, 88-95.
- 8Pazienza V, Vinciguerra M, Mazzoccoli G.PPARs Signaling and Cancer in the Gastrointestinal System. , PPAR Res 2012, 560846.
- 9Tung S, Shi Y, Wong K, Zhu F, Gorczynski R et al.PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. , Blood 2013, 969-80.
- 10Spaner D E, Lee E, Shi Y, Wen F, Li Y et al.PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia. , Leukemia 2013, 1090-9.
- 11Chen Q, Yuan Y, Chen T Morphology.differentiation and adhesion molecule expression changes of bone marrow mesenchymal stem cells from acute myeloid leukemia patients. , Mol Med Rep 2014, 293-8.
- 12Ito K, Carracedo A, Weiss D, Arai F, Ala U et al.A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. , Nat Med 2012, 1350-8.
- 13Yoo S H, Park O, Henderson L E, Abdelmegeed M A, Moon K-H et al.Lack of PPARα exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress. , Toxicol Lett 2011, 23-9.
- 14Wu L, Yan C, Czader M, Foreman O, Blum J S et al.Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. , Blood 2012, 115-26.
- 15Zak Z, Gelebart P, Lai R.Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NF-kappaB signaling axis. , Leukemia 2010, 1476-86.
- 16McKay L I, Cidlowski J A.Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. , Endocr Rev 1999, 435-59.
- 17Copland J A, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G et al.Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? BioEssays News Rev Mol Cell Dev Biol. 2009, 629-41.
- 18Logotheti S, Papaevangeliou D, Michalopoulos I, Sideridou M, Tsimaratou K et al. (2012) Progression of mouse skin carcinogenesis is associated with increased ERα levels and is repressed by a dominant negative form of ERα. , PloS One
- 19Khan S, Lopez-Dee Z, Kumar R, Ling J.Activation of NFkB is a novel mechanism of pro-survival activity of glucocorticoids in breast cancer cells. , Cancer Lett 2013, 90-5.
- 20Papi A, Guarnieri T, Storci G, Santini D, Ceccarelli C et al.Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells. , Cell Death Differ 2012, 1208-19.
- 21Yang Y, Groshong J S, Matta H, Gopalakrishnan R, Yi H et al.Constitutive NF-kappaB activation confers interleukin 6 (IL6) independence and resistance to dexamethasone and Janus kinase inhibitor INCB018424 in murine plasmacytoma cells. , J Biol Chem 2011, 27988-97.
- 22Kamieńska E, Ociepa T, Wysocki M, Kurylak A, Matysiak M et al.Activation of NF-ĸB in leukemic cells in response to initial prednisone therapy in children with acute lymphoblastic leukaemia: relation to other prognostic factors. , Pol J Pathol Off J Pol Soc Pathol 2011, 5-11.
- 23Kapelko-Słowik K, Urbaniak-Kujda D, Wołowiec D, Jaźwiec B, Dybko J et al.Expression of PIM-2 and NF-κB genes is increased in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is associated with complete remission rate and overall survival. Postȩpy Hig Med Dośw Online 2013;67:. 553-9.
- 24MCJ Bosman, Schuringa J J, Quax W J, Vellenga E.Bortezomib sensitivity of acute myeloid leukemia CD34(+) cells can be enhanced by targeting the persisting activity of NF-κB and the accumulation of MCL-1. Exp Hematol 2013;41:. 530-538.
- 25Cariello N F, Romach E H, Colton H M, Ni H, Yoon L et al.Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver. , Toxicol Sci Off J Soc Toxicol 2005, 250-64.
- 26Genovese T, Esposito E, Mazzon E, Crisafulli C, Paterniti I et al.PPAR-alpha modulate the anti-inflammatory effect of glucocorticoids in the secondary damage in experimental spinal cord trauma. , Pharmacol Res Off J Ital Pharmacol Soc 2009, 338-50.
- 27Hatano Y, Elias P M, Crumrine D, Feingold K R, Katagiri K et al.Efficacy of combined peroxisome proliferator-activated receptor-α ligand and glucocorticoid therapy in a murine model of atopic dermatitis. , J Invest Dermatol 2011, 1845-52.
- 28Bougarne N, Paumelle R, Caron S, Hennuyer N, Mansouri R et al.PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB. , Proc Natl Acad Sci U S A 2009, 7397-402.
- 29Lambrou G I, Vlahopoulos S, Papathanasiou C, Papanikolaou M, Karpusas M et al.Prednisolone exerts late mitogenic and biphasic effects on resistant acute lymphoblastic leukemia cells: Relation to early gene expression. , Leuk Res 2009, 1684-95.
- 30Lambrou G I, Papadimitriou L, Chrousos G P, Vlahopoulos S A.Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators. , Mol Cell Endocrinol 2012, 142-51.
- 31Messinger Y H, Gaynon P S, Sposto R, Giessen J van der, Eckroth E et al.Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia:. Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood 2012, 285-90.
- 32Manshouri T, Estrov Z, Quintás-Cardama A, Burger J, Zhang Y et al.Bone marrow stroma-secreted cytokines protect JAK2(V617F)-mutated cells from the effects of a JAK2 inhibitor. , Cancer Res 2011, 3831-40.
- 33Gervois P, Kleemann R, Pilon A, Percevault F, Koenig W et al.Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate. , J Biol Chem 2004, 16154-60.
- 34Ratman D, Vanden Berghe W, Dejager L, Libert C, Tavernier J et al.How glucocorticoid receptors modulate the activity of other transcription factors: A scope beyond tethering. , Mol Cell Endocrinol 2013, 41-54.