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Lercanidipine alleviates doxorubicin-induced lung injury by regulating PERK/CHOP and Bax/Bcl 2/Cyt c pathways

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Abstract

Doxorubicin (DOX), which is used to treat various cancers and hematological malignancies, has limited therapeutic application due to its toxicity in tissues and organs. These toxic effects occur through alterations in intracellular calcium regulation, elevated cell stress and oxidative damage, and increased apoptosis. Lercanidipine (LRD) is a long-acting antihypertensive calcium channel blocker with anti-inflammatory, anti-apoptotic, and antioxidant effects. The aim of this study was to investigate the effect of LRD on DOX-induced lung toxicity. Four groups (control, DOX, DOX + 0.5 LRD, and DOX + 2 LRD) totaling 32 rats were established. TNF-α levels in the lung tissues were detected by immunohistochemistry, and the tissues were subjected to histopathological examination. In determining oxidative stress, total antioxidant status (TAS) and total oxidative stress (TOS) were determined using spectrophotometry, and the oxidative stress index (OSI) value was calculated. The mRNA relative expression levels of the genes were evaluated by RT-qPCR. It was determined that inflammatory and oxidative stress markers and pro-apoptotic gene levels were increased and anti-apoptotic gene levels were decreased in the lung tissues of the DOX-administered group. In addition, histopathological changes were significantly increased. Although it was not statistically significant, inflammation, oxidative stress, and apoptosis were reduced, as were other histopathological indicators, in the group that received LRD (0.5 mg/kg). Inflammation, oxidative stress, and apoptosis were found to be statistically reduced and corroborated by histological findings in the group given LRD (2 mg/kg). In conclusion, it was determined that LRD had an ameliorative effect on DOX-induced lung toxicity in an experimental animal model.

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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  • Altindag O, Erel O, Soran N et al (2008) Total oxidative/anti-oxidative status and relation to bone mineral density in osteoporosis. Rheumatol Int 28:317–321

    Article  CAS  PubMed  Google Scholar 

  • Benzer F, Kandemir FM, Kucukler S et al (2018) Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem 124:448–457

    Article  CAS  PubMed  Google Scholar 

  • Borghi C (2005) Lercanidipine in hypertension. Vasc Health Risk Manag 1:173

    CAS  PubMed  PubMed Central  Google Scholar 

  • Childs AC, Phaneuf SL, Dirks AJ et al (2002) Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2: Bax ratio. Cancer Res 62:4592–4598

    CAS  PubMed  Google Scholar 

  • Gupta S, Sharma U, Jagannathan NR, Gupta YK (2017) Neuroprotective effect of lercanidipine in middle cerebral artery occlusion model of stroke in rats. Exp Neurol 288:25–37

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Wu Q, Wang Z et al (2019) Inhibition of CACNA1H attenuates doxorubicin-induced acute cardiotoxicity by affecting endoplasmic reticulum stress. Biomed Pharmacother 120:109475

    Article  CAS  PubMed  Google Scholar 

  • İlhan İ, Halil A, Sevük MA et al (2022) Doksorubisin ile oluşturulan böbrek hasarında lerkanidipinin antioksidan ve antiapoptotik etkilerinin bcl-2/bax/sit c/cas-3 yolağı üzerinden araştırılması. SDÜ Tıp Fakültesi Derg 29:671–679

    Article  Google Scholar 

  • Injac R, Radic N, Govedarica B et al (2009) Acute doxorubicin pulmotoxicity in rats with malignant neoplasm is effectively treated with fullerenol C60 (OH) 24 through inhibition of oxidative stress. Pharmacol Reports 61:335–342

    Article  CAS  Google Scholar 

  • Karakuyu NF, Savran M, Candan IA et al (2023) Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity. Naunyn Schmiedebergs Arch Pharmacol. https://doi.org/10.1007/s00210-023-02566-7

    Article  PubMed  Google Scholar 

  • Martinez MLL, Lopes LF, Coelho EB et al (2006) Lercanidipine reduces matrix metalloproteinase-9 activity in patients with hypertension. J Cardiovasc Pharmacol 47:117–122

    Article  CAS  PubMed  Google Scholar 

  • Mason RP (1999) Effects of calcium channel blockers on cellular apoptosis: implications for carcinogenic potential. Cancer 85:2093–2102

    Article  CAS  PubMed  Google Scholar 

  • Olson RD, Mushlin PS, Brenner DE et al (1988) Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci 85:3585–3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rashid S, Ali N, Nafees S et al (2013) Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats. Toxicol Mech Methods 23:337–345

    Article  CAS  PubMed  Google Scholar 

  • Robles NR, Ocon J, Gomez CF et al (2005) Lercanidipine in patients with chronic renal failure: the ZAFRA study. Ren Fail 27:73–80

    Article  CAS  PubMed  Google Scholar 

  • Selvaraj N, Adhimoolam M, Perumal DK, Rajamohammed MA (2015) Neuroprotective effect of lercanidipine-A novel calcium channel blocker in Albino Mice. J Clin Diagnostic Res 9:FF01

    CAS  Google Scholar 

  • Sonkusare S, Srinivasan K, Kaul C, Ramarao P (2005) Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life Sci 77:1–14

    Article  CAS  PubMed  Google Scholar 

  • Srdjenovic B, Milic-Torres V, Grujic N et al (2010) Antioxidant properties of fullerenol C60 (OH) 24 in rat kidneys, testes, and lungs treated with doxorubicin. Toxicol Mech Methods 20:298–305

    Article  CAS  PubMed  Google Scholar 

  • Tangpong J, Cole MP, Sultana R et al (2006) Adriamycin-induced, TNF-α-mediated central nervous system toxicity. Neurobiol Dis 23:127–139

    Article  CAS  PubMed  Google Scholar 

  • Tepebaşı MY, Büyükbayram Hİ, Özmen Ö et al (2023) Dexpanthenol ameliorates doxorubicin-induced lung injury by regulating endoplasmic reticulum stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol 396:1837–1845

    Article  PubMed  Google Scholar 

  • Tsukamoto Y, Kiyasu J, Choi I et al (2020) Efficacy and safety of the modified EPOCH regimen (etoposide, vincristine, doxorubicin, carboplatin, and prednisolone) for adult T-cell leukemia/lymphoma: a multicenter retrospective study. Clin Lymphoma Myeloma Leuk 20:e445–e453

    Article  PubMed  Google Scholar 

  • Viereckl M, Alojibaily N, Hydock D, Han Y (2020) The role of creatine supplementation in alleviating doxorubicin ınduced hepatotoxicity. FASEB J. https://doi.org/10.1096/fasebj.2020.34.s1.06416

    Article  Google Scholar 

  • Wang Z, Wang M, Liu J et al (2018) Inhibition of TRPA1 attenuates doxorubicin-induced acute cardiotoxicity by suppressing oxidative stress, the inflammatory response, and endoplasmic reticulum stress. Oxid Med Cell Longev. https://doi.org/10.1155/2018/5179468

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang H, Dou S, Zhu J et al (2021) Regulatory effects of ghrelin on endoplasmic reticulum stress, oxidative stress, and autophagy: Therapeutic potential. Neuropeptides 85:102112

    Article  CAS  PubMed  Google Scholar 

  • Warpe VS, Mali VR, Arulmozhi S et al (2015) Cardioprotective effect of ellagic acid on doxorubicin induced cardiotoxicity in wistar rats. J Acute Med 5:1–8

    Article  Google Scholar 

  • Xu Z-M, Li C-B, Liu Q-L et al (2018) Ginsenoside Rg1 prevents doxorubicin-induced cardiotoxicity through the inhibition of autophagy and endoplasmic reticulum stress in mice. Int J Mol Sci 19:3658

    Article  PubMed  PubMed Central  Google Scholar 

  • Yalçın A, Ahmet T, Aydın H et al (2020) Effects of Vitamin D on doxorubucin-induced lung injury and TRPM2 immunoreactivity in rats. J Surg Med 4:1236–1239

    Article  Google Scholar 

  • Yarmohammadi F, Rezaee R, Haye AW, Karimi G (2021) Endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity may be therapeutically targeted by natural and chemical compounds: a review. Pharmacol Res 164:105383

    Article  CAS  PubMed  Google Scholar 

  • Zawadzki A, Liu Q, Wang Y et al (2008) Verapamil inhibits L-type calcium channel mediated apoptosis in human colon cancer cells. Dis Colon Rectum 51:1696–1702

    Article  PubMed  Google Scholar 

  • Zhang K (2010) Integration of ER stress, oxidative stress and the inflammatory response in health and disease. Int J Clin Exp Med 3:33

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Genetics, University of Süleyman Demirel, 32300, Isparta, Turkey

    Muhammet Yusuf Tepebaşı

  2. Department of Histology and Embryology, University of Alaaddin Keykubat, Alanya, Turkey

    Jale Selli

  3. Medical School, University of Süleyman Demirel, Isparta, Turkey

    Salih Gül & İbrahim Hüseynov

  4. Department of Pathology, University of Mehmet Akif Ersoy, Burdur, Turkey

    Adem Milletsever

  5. Department of Medical Biology, University of Süleyman Demirel, Isparta, Turkey

    Esma Selçuk

Authors
  1. Muhammet Yusuf Tepebaşı
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  2. Jale Selli
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  3. Salih Gül
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  4. İbrahim Hüseynov
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  5. Adem Milletsever
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  6. Esma Selçuk
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Contributions

All authors contributed at all stages of the study. All of the authors contributed to the design of the study, the collection of samples, the analysis, and the interpretation of data. MT and ES experiment planning, statistical analysis and genetic analysis, JS and AM histopathological and immunohistochemical analyses, SG and IH experimental animal applications.

Corresponding author

Correspondence to Muhammet Yusuf Tepebaşı.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose. Dr. Tepebasi and the co-authors have no conflicts of interest to declare in association with this study.

Ethical approval

The animal experiments were approved by the local animal ethics committee of Suleyman Demirel University (no: 15.09.2022/06–81). The authors declare that the procedures were followed according to the regulations established by the Clinical Research and Ethics Committee and to the Helsinki Declaration of the World Medical Association updated in 2013.

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Tepebaşı, M.Y., Selli, J., Gül, S. et al. Lercanidipine alleviates doxorubicin-induced lung injury by regulating PERK/CHOP and Bax/Bcl 2/Cyt c pathways. Histochem Cell Biol 160, 361–368 (2023). https://doi.org/10.1007/s00418-023-02231-3

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  • DOI: https://doi.org/10.1007/s00418-023-02231-3

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