Fenofibrate attenuates the cytotoxic effect of cisplatin on lung cancer cells by enhancing the antioxidant defense system <em>in vitro</em>

Kogami,Mariko; Abe,Shinji; Nakamura,Hiroyuki; Aoshiba,Kazutetsu

doi:10.3892/ol.2023.13899

Fenofibrate attenuates the cytotoxic effect of cisplatin on lung cancer cells by enhancing the antioxidant defense system in vitro

Authors:
- Mariko Kogami
- Shinji Abe
- Hiroyuki Nakamura
- Kazutetsu Aoshiba
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Affiliations: Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki 300‑0395, Japan, Department of Respiratory Medicine, Tokyo Medical University, Tokyo 160‑0023, Japan, Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki 300‑0395, Japan
Published online on: June 6, 2023 https://doi.org/10.3892/ol.2023.13899
Article Number: 313
Copyright: © Kogami et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fenofibrate (FF) is a peroxisome proliferator‑ activated receptor (PPAR)‑α agonist that is widely used for the treatment of hyperlipidemia. It has been shown to have pleiotropic actions beyond its hypolipidemic effect. FF has been shown to exert a cytotoxic effect on some cancer cells when used at higher than clinically relevant concentrations; on the other hand, its cytoprotective effect on normal cells has also been reported. The present study assessed the effect of FF on cisplatin (CDDP) cytotoxicity to lung cancer cells in vitro. The results demonstrated that the effect of FF on lung cancer cells depends on its concentration. FF at ≤50 µM, which is a clinically achievable blood concentration, attenuated CDDP cytotoxicity to lung cancer cells, whereas FF at ≥100 µM, albeit clinically unachievable, had an anticancer effect. The mechanism of FF attenuation of CDDP cytotoxicity involved PPAR‑α‑dependent aryl hydrocarbon receptor (AhR) expression, which in turn stimulated nuclear factor erythroid 2‑related factor 2 (Nrf2) expression and antioxidant production, resulting in lung cancer cell protection from CDDP‑evoked oxidative damage. In conclusion, the present study revealed that FF, at clinically relevant concentrations, attenuated CDDP cytotoxicity to lung cancer cells by enhancing the antioxidant defense system through activation of a pathway that involves the PPAR‑α‑PPAR response element‑AhR xenobiotic response element‑Nrf2‑antioxidant response element. These findings suggested that concomitant use of FF with CDDP may compromise the efficacy of chemotherapy. Although the anticancer property of FF has recently attracted much attention, concentrations that exceed clinically relevant concentrations are required.

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1	Patsouris D, Mandard S, Voshol PJ, Escher P, Tan NS, Havekes LM, Koenig W, März W, Tafuri S, Wahli W, et al: PPARalpha governs glycerol metabolism. J Clin Invest. 114:94–103. 2004. View Article : Google Scholar : PubMed/NCBI
2	Koltai T: Fenofibrate in cancer: Mechanisms involved in anticancer activity. F1000Res. 4:552015. View Article : Google Scholar
3	Abdel Magid AM, Abbassi MM, Iskander EEM, Mohamady O and Farid SF: Randomized comparative efficacy and safety study of intermittent simvastatin versus fenofibrate in hemodialysis. J Comp Eff Res. 6:413–424. 2017. View Article : Google Scholar : PubMed/NCBI
4	Noonan JE, Jenkins AJ, Ma JX, Keech AC, Wang JJ and Lamoureux EL: An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes. Diabetes. 62:3968–3975. 2013. View Article : Google Scholar : PubMed/NCBI
5	Lian X, Wang G, Zhou H, Zheng Z, Fu Y and Cai L: Anticancer roperties of fenofibrate: A repurposing use. J Cancer. 9:1527–1537. 2018. View Article : Google Scholar : PubMed/NCBI
6	Vlase L, Popa A, Muntean D and Leucuta SE: Pharmacokinetics and comparative bioavailability of two fenofibrate capsule formulations in healthy volunteers. Arzneimittelforschung. 60:560–563. 2010.PubMed/NCBI
7	Davies SP, Mycroft-West CJ, Pagani I, Hill HJ, Chen YH, Karlsson R, Bagdonaite I, Guimond SE, Stamataki Z, De Lima MA, et al: The hyperlipidaemic drug fenofibrate significantly reduces infection by SARS-CoV-2 in cell culture models. Front Pharmacol. 12:6604902021. View Article : Google Scholar : PubMed/NCBI
8	Luty M, Piwowarczyk K, Łabędź-Masłowska A, Wróbel T, Szczygieł M, Catapano J, Drabik G, Ryszawy D, Kędracka-Krok S, Madeja Z, et al: Fenofibrate augments the sensitivity of drug-resistant prostate cancer cells to docetaxel. Cancers (Basel). 11:772019. View Article : Google Scholar : PubMed/NCBI
9	Balakumar P, Sambathkumar R, Mahadevan N, Muhsinah AB, Alsayari A, Venkateswaramurthy N and Dhanaraj SA: Molecular targets of fenofibrate in the cardiovascular-renal axis: A unifying perspective of its pleiotropic benefits. Pharmacol Res. 144:132–141. 2019. View Article : Google Scholar : PubMed/NCBI
10	Li J, Wang P, Chen Z, Yu S and Xu H: Fenofibrate ameliorates oxidative stress-induced retinal microvascular dysfunction in diabetic rats. Curr Eye Res. 43:1395–1403. 2018. View Article : Google Scholar : PubMed/NCBI
11	Sekulic-Jablanovic M, Petkovic V, Wright MB, Kucharava K, Huerzeler N, Levano S, Brand Y, Leitmeyer K, Glutz A, Bausch A and Bodmer D: Effects of peroxisome proliferator activated receptors (PPAR)-γ and -α agonists on cochlear protection from oxidative stress. PLOS One. 12:e01885962017. View Article : Google Scholar : PubMed/NCBI
12	Hsu YJ, Lin CW, Cho SL, Yang WS, Yang CM and Yang CH: Protective effect of fenofibrate on oxidative stress-induced apoptosis in retinal-choroidal vascular endothelial cells: Implication for diabetic retinopathy treatment. Antioxidants (Basel). 9:7122020. View Article : Google Scholar : PubMed/NCBI
13	Cortes-Lopez F, Sanchez-Mendoza A, Centurion D, Cervantes-Perez LG, Castrejon-Tellez V, Del Valle-Mondragon L, Soria-Castro E, Ramirez V, Sanchez-Lopez A, Pastelin-Hernandez G, et al: Fenofibrate protects cardiomyocytes from hypoxia/reperfusion- and high glucose-induced detrimental effects. PPAR Res. 2021:88953762021. View Article : Google Scholar : PubMed/NCBI
14	Thongnuanjan P and Soodvilai S, Chatsudthipong V and Soodvilai S: Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways. J Toxicol Sci. 41:339–349. 2016. View Article : Google Scholar : PubMed/NCBI
15	Kim SJ, Park C, Lee JN and Park R: Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction. Toxicol Appl Pharmacol. 353:43–54. 2018. View Article : Google Scholar : PubMed/NCBI
16	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Desager JP, Horsmans Y, Vandenplas C and Harvengt C: Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days. Atherosclerosis. 124 (Suppl):S65–S73. 1996. View Article : Google Scholar : PubMed/NCBI
19	Ivashkevich A, Redon CE, Nakamura AJ, Martin RF and Martin OA: Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Lett. 327:123–133. 2012. View Article : Google Scholar : PubMed/NCBI
20	Yip KW and Reed JC: Bcl-2 family proteins and cancer. Oncogene. 27:6398–6406. 2008. View Article : Google Scholar : PubMed/NCBI
21	Endo H, Yano M, Okumura Y and Kido H: Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70. Cell Death Dis. 5:e10272014. View Article : Google Scholar : PubMed/NCBI
22	Berndtsson M, Hägg M, Panaretakis T, Havelka AM, Shoshan MC and Linder S: Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer. 120:175–180. 2007. View Article : Google Scholar : PubMed/NCBI
23	Kikuchi R, Iwai Y, Tsuji T, Watanabe Y, Koyama N, Yamaguchi K, Nakamura H and Aoshiba K: Hypercapnic tumor microenvironment confers chemoresistance to lung cancer cells by reprogramming mitochondrial metabolism in vitro. Free Radic Biol Med. 134:200–214. 2019. View Article : Google Scholar : PubMed/NCBI
24	Fujii J, Homma T and Osaki T: Superoxide radicals in the execution of cell death. Antioxidants(Basel). 11:5012022. View Article : Google Scholar : PubMed/NCBI
25	Shaw P and Chattopadhyay A: Nrf2-ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. J Cell Physiol. 235:3119–3130. 2020. View Article : Google Scholar : PubMed/NCBI
26	Lee C: Collaborative power of Nrf2 and PPARγ activators against metabolic and drug-Induced oxidative injury. Oxid Med Cell Longev. 2017:13781752017. View Article : Google Scholar : PubMed/NCBI
27	Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K and Yamamoto M: Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 24:7130–7139. 2004. View Article : Google Scholar : PubMed/NCBI
28	Taguchi K and Yamamoto M: The KEAP1-NRF2 system in cancer. Front Oncol. 7:852017. View Article : Google Scholar : PubMed/NCBI
29	Probst BL, McCauley L, Trevino I, Wigley WC and Ferguson DA: Cancer cell growth is differentially affected by constitutive activation of NRF2 by KEAP1 deletion and pharmacological activation of NRF2 by the synthetic triterpenoid, RTA 405. PLoS One. 10:e01352572015. View Article : Google Scholar : PubMed/NCBI
30	Wang R, An J, Ji F, Jiao H, Sun H and Zhou D: Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun. 373:151–154. 2008. View Article : Google Scholar : PubMed/NCBI
31	Miao W, Hu L, Scrivens PJ and Batist G: Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: Direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem. 280:20340–20348. 2005. View Article : Google Scholar : PubMed/NCBI
32	Larigot L, Juricek L, Dairou J and Coumoul X: AhR signaling pathways and regulatory functions. Biochim Open. 7:1–9. 2018. View Article : Google Scholar : PubMed/NCBI
33	Villard PH, Caverni S, Baanannou A, Khalil A, Martin PG, Penel C, Pineau T, Seree E and Barra Y: PPARalpha transcriptionally induces AhR expression in Caco-2, but represses AhR pro-inflammatory effects. Biochem Biophys Res Commun. 364:896–901. 2007. View Article : Google Scholar : PubMed/NCBI
34	Coelho NR, Pimpão AB, Correia MJ, Rodrigues TC, Monteiro EC, Morello J and Pereira SA: Pharmacological blockage of the AHR-CYP1A1 axis: A call for in vivo evidence. J Mol Med (Berl). 100:215–243. 2022. View Article : Google Scholar : PubMed/NCBI
35	Terashima J, Habano W, Gamou T and Ozawa S: Induction of CYP1 family members under low-glucose conditions requires AhR expression and occurs through the nuclear translocation of AhR. Drug Metab Pharmacokinet. 26:577–583. 2011. View Article : Google Scholar : PubMed/NCBI
36	Majeed Y, Upadhyay R, Alhousseiny S, Taha T, Musthak A, Shaheen Y, Jameel M, Triggle CR and Ding H: Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro. Sci Rep. 9:63162013. View Article : Google Scholar
37	Kikuchi R, Maeda Y, Tsuji T, Yamaguchi K, Abe S, Nakamura H and Aoshiba K: Fenofibrate inhibits TGF-β-induced myofibroblast differentiation and activation in human lung fibroblasts in vitro. FEBS Open Bio. 11:2340–2349. 2021.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
38	Raghunath A, Sundarraj K, Nagarajan R, Arfuso F, Bian J, Kumar AP, Sethi G and Perumal E: Antioxidant response elements: Discovery, classes, regulation and potential applications. Redox Biol. 17:297–314. 2018. View Article : Google Scholar : PubMed/NCBI
39	Park JS, Kang DH, Lee DH and Bae SH: Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation. Biochem Biophys Res Commun. 465:542–547. 2015. View Article : Google Scholar : PubMed/NCBI
40	Kim T and Yang Q: Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. World J Cardiol. 5:164–174. 2013. View Article : Google Scholar : PubMed/NCBI
41	Kim YH, Yoo HY, Chang MS, Jung G and Rho HM: C/EBP alpha is a major activator for the transcription of rat Cu/Zn superoxide dismutase gene in liver cell. FEBS Lett. 401:267–270. 1997. View Article : Google Scholar : PubMed/NCBI
42	Ding G, Fu M, Qin Q, Lewis W, Kim HW, Fukai T, Bacanamwo M, Chen YE, Schneider MD, Mangelsdorf DJ, et al: Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage. Cardiovasc Res. 76:269–279. 2007. View Article : Google Scholar : PubMed/NCBI
43	Girnun GD, Domann FE, Moore SA and Robbins ME: Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. Mol Endocrinol. 16:2793–2801. 2002. View Article : Google Scholar : PubMed/NCBI
44	Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M and Kensler TW: NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis. Mol Cell Biol. 27:7188–7197. 2007. View Article : Google Scholar : PubMed/NCBI
45	Ma Q: Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 53:401–26. 2013. View Article : Google Scholar : PubMed/NCBI
46	Sun C, Song B, Sheng W, Yu D, Yang T, Geng F, Fang K, Jiao Y, Zhang J and Zhang S: Fenofibrate attenuates radiation-induced oxidative damage to the skin through fatty acid binding protein 4 (FABP4). Front Biosci (Landmark Ed). 27:2142022. View Article : Google Scholar : PubMed/NCBI
47	Kadian S, Mahadevan N and Balakumar P: Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy. Eur J Pharmacol. 698:388–396. 2013. View Article : Google Scholar : PubMed/NCBI
48	Ibarra-Lara L, Sánchez-Aguilar M, Sánchez-Mendoza A, Del Valle-Mondragón L, Soria-Castro E, Carreón-Torres E, Díaz-Díaz E, Vázquez-Meza H, Guarner-Lans V and Rubio-Ruiz ME: Fenofibrate therapy restores antioxidant protection and improves myocardial insulin resistance in a rat model of metabolic syndrome and myocardial ischemia: The role of angiotensin II. Molecules. 22:312016. View Article : Google Scholar : PubMed/NCBI