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Doxorubicin and doxorubicin-loaded nanoliposome induce senescence by enhancing oxidative stress, hepatotoxicity, and in vivo genotoxicity in male Wistar rats

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Abstract

The senescence phenomenon is historically considered as a tumor-suppressing mechanism that can permanently arrest the proliferation of damaged cells, and prevent tumor eradication by activating cell cycle regulatory pathways. Doxorubicin (DX) as an antineoplastic agent has been used for the treatment of solid and hematological malignancies for a long time, but its clinical use is limited due to irreversible toxicity on off-target tissues. Thereby, the encapsulation of plain drugs in a vehicle may decrease the side effects while increasing their permeability and availability in target cells. Here, we aimed to investigate and compare the effects of DX and DX-loaded nanoliposome (NLDX) on the induction of senescence via assessment of the occurrence of apoptosis/necrosis, genomic damage, oxidative stress, and liver pathologies. The study groups included DX (0.75, 0.5, 0.1 mg/kg/BW), NLDX groups (0.1, 0.05, 0.025 mg/kg/BW), and an untreated control group. The liver tissues were used to investigate the oxidative stress parameters and probable biochemical and histopathological alterations. Annexin V/PI staining was carried out to find the type of cellular death in the liver tissue of healthy rats exposed to different concentrations of DOX and LDOX. Data revealed that the highest dose of NLDX (0.1 mg/kg/BW) could significantly induce cellular senescence throughout significant increasing the level of genotoxic damage (p < 0.0001) and the oxidative stress (p < 0.001) compared with a similar dose of DX, in which the obtained results were further confirmed by flow cytometry and histopathological assessments of the liver tissue. This investigation provides sufficient evidence of improved therapeutic efficacy of NLDX compared with plain DX in male Wistar rats.

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All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Funding

This work was funded by the Pharmaceutical Sciences Research Center and Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran.

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Authors and Affiliations

  1. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Mohammad Shokrzadeh & Nasrin Ghassemi-Barghi

  2. Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Abouzar Bagheri

  3. Pharmaceutical Sciences Research Center, Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran

    Nazanin Rahmanian

  4. Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran

    Morteza Eskandani PhD

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  1. Mohammad Shokrzadeh
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  2. Abouzar Bagheri
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  4. Nazanin Rahmanian
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  5. Morteza Eskandani PhD
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Contributions

MS and ME conceived and designed research. NR, AB, and NG-B conducted experiments. MS and NR analyzed data. NR and ME wrote and edited the manuscript. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

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Correspondence to Nazanin Rahmanian or Morteza Eskandani PhD.

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All the animal experimental procedures were conducted according to the general guidelines of the Animal Ethics Committee of Mazandaran University of Medical Sciences (IR.MAZUMS.REC.1399.7010) and carried out in accordance with the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978).

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Shokrzadeh, M., Bagheri, A., Ghassemi-Barghi, N. et al. Doxorubicin and doxorubicin-loaded nanoliposome induce senescence by enhancing oxidative stress, hepatotoxicity, and in vivo genotoxicity in male Wistar rats. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1803–1813 (2021). https://doi.org/10.1007/s00210-021-02119-w

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