Advertisement

β-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD+/AMPK/NF-kB in mice

  • Davoud Sanajou
  • Saeed Nazari Soltan Ahmad
  • Vahid Hosseini
  • Ashkan Kalantary-Charvadeh
  • Yasser Marandi
  • Leila Roshangar
  • Saman Bahrambeigi
  • Mehran Mesgari-AbbasiEmail author
Original Article
  • 34 Downloads

Abstract

β-Lapachone (B-LAP) is a natural naphtaquinone with established anti-oxidative stress and anti-cancer activities. We aimed to investigate B-LAP protective potential against doxorubicin (DOX)-induced nephrotoxicity in mice. The mice received an oral dose of B-LAP followed by a single intraperitoneal injection of 20 mg/kg DOX a day later. They were then treated for 4 days with 1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg doses of B-LAP. Renal levels of NAD+/NADH ratios, p-AMPKα, p-NF-κB p65, inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) along with renal expressions of TNF-α, IL-1β, and IL-6 were examined. Serum levels of kidney function markers as well as renal histopathology were also investigated. In addition to increasing the activities of p-AMPKα, B-LAP elevated NAD+/NADH ratios in the kidneys and decreased the renal levels of nuclear p-NF-κB and its correspondent downstream effectors TNF-α, IL-1β, IL-6, and iNOS in the kidneys. Also, B-LAP effectively ameliorated renal architectural changes and attenuated serum levels of urea, creatinine, and cystatin C. Collectively, these findings suggest the protective actions of B-LAP against DOX-induced nephrotoxicity in mice.

Keywords

β-Lapachone Doxorubicin NAD+/NADH ratio Nephrotoxicity 

Notes

Funding information

This work was supported with grants from the Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Compliance with ethical standards

The housing conditions and animal care procedures were set according to the protocols issued by the Tabriz University of Medical Sciences and approved by the Animal Ethics Council of the university.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Albadine R, Wang W, Brownlee NA, Toubaji A, Billis A, Argani P, Epstein JI, Garvin AJ, Cousi R, Schaeffer EM (2009) Topoisomerase II α status in renal medullary carcinoma: immuno-expression and gene copy alterations of a potential target of therapy. J Urol 182:735–740CrossRefGoogle Scholar
  2. Ayla S, Seckin I, Tanriverdi G, Cengiz M, Eser M, Soner BC, Oktem G (2011) Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. Int J Cell Biol:2011Google Scholar
  3. Cassidy H, Radford R, Slyne J, O’Connell S, Slattery C, Ryan MP, McMorrow T (2012) The role of MAPK in drug-induced kidney injury. Journal of Signal Transduction:2012Google Scholar
  4. Chen Y, Liu H, Zhang H, Liu E, Xu C-B, Su X (2016) The sirt1/NF-kB signaling pathway is involved in regulation of endothelin type B receptors mediated by homocysteine in vascular smooth muscle cells. Biomed Pharmacother 84:1979–1985CrossRefGoogle Scholar
  5. Choi BT, Cheong J, Choi YH (2003) β-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-κB in human colon cancer HCT-116 cells. Anti-Cancer Drugs 14:845–850CrossRefGoogle Scholar
  6. Chung W-B, Youn H-J (2016) Pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity. The Korean Journal of Internal Medicine 31:625–633CrossRefGoogle Scholar
  7. El-Sayed ESM, Mansour AM, El-Sawy WS (2017) Protective effect of proanthocyanidins against doxorubicin-induced nephrotoxicity in rats. J Biochem Mol Toxicol 31:e21965CrossRefGoogle Scholar
  8. Fan Y, Zhang Q (2013) Development of liposomal formulations: from concept to clinical investigations. Asian Journal of Pharmaceutical Sciences 8:81–87CrossRefGoogle Scholar
  9. Gerber DE, Bisen AK, Beg MS, Frankel AE, Fatunde O, Fattah F, Arriaga YE, Dowell J, Meek C, Bolluyt JD (2017) Phase 1 study of ARQ 761, a β-lapachone analog that promotes NQO1-mediated programmed cancer cell necrosis. In: American Society of Clinical Oncology, vol 35, p 2517Google Scholar
  10. Gratia S, Kay L, Potenza L, Seffouh A, Novel-Chate V, Schnebelen C, Sestili P, Schlattner U, Tokarska-Schlattner M (2012) Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress. Cardiovasc Res 95:290–299CrossRefGoogle Scholar
  11. Huang K, Gao X, Wei W (2017) The crosstalk between sirt1 and keap1/Nrf2/are anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells. Exp Cell Res 361:63–72CrossRefGoogle Scholar
  12. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25:1939–1948CrossRefGoogle Scholar
  13. Lahoti TS, Patel D, Thekkemadom V, Beckett R, Ray SD (2012) Doxorubicin-induced in vivo nephrotoxicity involves oxidative stress-mediated multiple pro-and anti-apoptotic signaling pathways. Curr Neurovasc Res 9:282–295CrossRefGoogle Scholar
  14. Lee VW, Harris DC (2011) Adriamycin nephropathy: a model of focal segmental glomerulosclerosis. Nephrology 16:30–38CrossRefGoogle Scholar
  15. Lee J-s, Park AH, Lee S-H, Lee S-H, Kim J-H, Yang S-J, Yeom YI, Kwak TH, Lee D, Lee S-J (2012) Beta-lapachone, a modulator of NAD metabolism, prevents health declines in aged mice. PLoS One e47122:7Google Scholar
  16. Li Y, Sun X, LaMont JT, Pardee AB, Li CJ (2003) Selective killing of cancer cells by β-lapachone: direct checkpoint activation as a strategy against cancer. Proc Natl Acad Sci 100:2674–2678CrossRefGoogle Scholar
  17. Liu J, Mao W, Ding B, Liang C-s (2008) ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Phys Heart Circ Phys 295:H1956–H1965Google Scholar
  18. Liu T, Zhang L, Joo D, Sun S-C (2017) NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy 2:17023CrossRefGoogle Scholar
  19. Lu CY (2014) β-Lapachone ameliorates murine cisplatin nephrotoxicity: NAD+, NQO1, and SIRT1 at the crossroads of metabolism, injury, and inflammation. Kidney Int 85:496–498CrossRefGoogle Scholar
  20. Ma Y, Chen H, He X, Nie H, Hong Y, Sheng C, Wang Q, Xia W, Ying W (2012) NAD+ metabolism and NAD+−dependent enzymes: promising therapeutic targets for neurological diseases. Curr Drug Targets 13:222–229CrossRefGoogle Scholar
  21. Mo C, Wang L, Zhang J, Numazawa S, Tang H, Tang X, Han X, Li J, Yang M, Wang Z (2014) The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal 20:574–588CrossRefGoogle Scholar
  22. Nazari Soltan Ahmad S, Rashtchizadeh N, Argani H, Roshangar L, Ghorbani Haghjo A, Sanajou D, Panah F, Ashrafi Jigheh Z, Dastmalchi S, Mesgari-Abbasi M (2018) Dunnione protects against experimental cisplatin-induced nephrotoxicity by modulating NQO1 and NAD+ levels. Free Radic Res:1–10Google Scholar
  23. Nozaki N, Shishido T, Takeishi Y, Kubota I (2004) Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2–knockout mice. Circulation 110:2869–2874CrossRefGoogle Scholar
  24. Oh G-S, Kim H-J, Choi J-H, Shen A, Choe S-K, Karna A, Lee SH, Jo H-J, Yang S-H, Kwak TH (2014) Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice. Kidney Int 85:547–560CrossRefGoogle Scholar
  25. Park E-J, Kwon H-K, Choi Y-M, Shin H-J, Choi S (2012) Doxorubicin induces cytotoxicity through upregulation of perk–dependent ATF3. PLoS One 7:e44990CrossRefGoogle Scholar
  26. Park J-S, Lee Y-Y, Kim J, Seo H, Kim H-S (2016) β-Lapachone increases phase II antioxidant enzyme expression via NQO1-AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes. Free Radic Biol Med 97:168–178CrossRefGoogle Scholar
  27. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690CrossRefGoogle Scholar
  28. Pugazhendhi A, Edison TNJI, Velmurugan BK, Jacob JA, Karuppusamy I (2018) Toxicity of doxorubicin (Dox) to different experimental organ systems. Life Sci 200:26–30CrossRefGoogle Scholar
  29. Queiroz ML, Valadares MC, Torello CO, Ramos AL, Oliveira AB, Rocha FD, Arruda VA, Accorci WR (2008) Comparative studies of the effects of Tabebuia avellanedae bark extract and β-lapachone on the hematopoietic response of tumour-bearing mice. J Ethnopharmacol 117:228–235CrossRefGoogle Scholar
  30. Salminen A, Hyttinen JM, Kaarniranta K (2011) AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med 89:667–676CrossRefGoogle Scholar
  31. Salomone F, Barbagallo I, Godos J, Lembo V, Currenti W, Cinà D, Avola R, D’Orazio N, Morisco F, Galvano F (2017) Silibinin restores NAD+ levels and induces the SIRT1/AMPK pathway in non-alcoholic fatty liver. Nutrients 9:1086CrossRefGoogle Scholar
  32. Singh K, Bhori M, Kasu YA, Bhat G, Marar T (2017) Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity-exploring the armoury of obscurity. Saudi Pharmaceutical JournalGoogle Scholar
  33. Su Z, Ye J, Qin Z, Ding X (2015) Protective effects of madecassoside against doxorubicin induced nephrotoxicity in vivo and in vitro. Sci Rep 5:18314CrossRefGoogle Scholar
  34. Sun J, Sun G, Cui X, Meng X, Qin M, Sun X (2016) Myricitrin protects against doxorubicin-induced cardiotoxicity by counteracting oxidative stress and inhibiting mitochondrial apoptosis via ERK/P53 pathway. Evidence-Based Complementary and Alternative Medicine 2016Google Scholar
  35. Sutton D, Wang S, Nasongkla N, Gao J, Dormidontova EE (2007) Doxorubicin and β-lapachone release and interaction with micellar core materials: experiment and modeling. Exp Biol Med 232:1090–1099CrossRefGoogle Scholar
  36. Suwei W, Kotamraju S, Konorev E, Kalivendi S, Joseph J, Kalyanaraman B (2002) Activation of nuclear factor-κB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochem J 367:729–740CrossRefGoogle Scholar
  37. Tacar O, Sriamornsak P, Dass CR (2013) Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol 65:157–170CrossRefGoogle Scholar
  38. Terai K, Dong G-Z, Oh E-T, Park M-T, Gu Y, Song CW, Park HJ (2009) Cisplatin enhances the anticancer effect of β-lapachone by upregulating NQO1. Anti-Cancer Drugs 20:901–909CrossRefGoogle Scholar
  39. Yang Y, Zhou X, Xu M, Piao J, Zhang Y, Lin Z, Chen L (2017) β-Lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 7:2681CrossRefGoogle Scholar
  40. Zhao L, Zhang B (2017) Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci Rep 7:44735CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Davoud Sanajou
    • 1
  • Saeed Nazari Soltan Ahmad
    • 1
  • Vahid Hosseini
    • 1
    • 2
  • Ashkan Kalantary-Charvadeh
    • 1
  • Yasser Marandi
    • 3
  • Leila Roshangar
    • 2
  • Saman Bahrambeigi
    • 4
  • Mehran Mesgari-Abbasi
    • 5
    Email author
  1. 1.Department of Biochemistry, Faculty of MedicineTabriz University of Medical SciencesTabrizIran
  2. 2.Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
  3. 3.Department of Biochemistry, Faculty of MedicineHamedan University of Medical SciencesHamedanIran
  4. 4.Department of Basic SciencesFaculty of Veterinary MedicineTabrizIran
  5. 5.Drug Applied Research CenterTabriz University of Medical SciencesTabrizIran

Personalised recommendations