Co-administration of Luteolin mitigated toxicity in rats' lungs associated with doxorubicin treatment

https://doi.org/10.1016/j.taap.2020.115380Get rights and content

Highlights

  • Doxorubicin (DOX) toxicity and Luteolin (LUT) was studied in rats' lung and blood.

  • Polyphenolic LUT, mitigated DOX-induced oxidative injury induced in rats' lungs.

  • LUT improved blood function and suppressed apoptosis response in DOX treated.

  • LUT suppressed DOX-mediated increases in pro-inflammation mediators.

  • LUT significantly abated DOX-mediated rat lungs histopathological damage.

Abstract

Doxorubicin (DOX), is a drug against lung malignancies with undesirable side effect including oxidative, inflammatory and apoptotic effects. Luteolin (LUT), present in fruits and vegetables is pharmacologically active against oxido-inflammatory and apoptotic responses. The present study examined the effect of LUT on DOX-induced lungs and blood dysfunction in Wistars rat (sex: male; 10 weeks old, 160 ± 5 g). Randomly grouped (n = 10) rats were treated as follows: control, LUT alone (100 mg/kg; per os), DOX (2 mg/kg; i. p), and co-treated rats with LUT (50 or 100 mg/kg) and DOX for two consecutive weeks. DOX alone adversely altered the final body and relative organ weights, red and white blood cell and platelet counts. DOX significantly (p > 0.05) reduced lungs antioxidant capacity, and anti-inflammatory cytokines; increased biomarkers of oxidative stress, caspase-3 activity, and pro-inflammatory cytokine. Morphological damages accompanied these biochemical alterations in the lung of experimental rats. Co-treatment with LUT, dose-dependently reversed DOX-mediated changes in rats' survival, toxic responses, and diminished oxidative stress in rat's lungs. Furthermore, co-treatment with LUT resulted in the reduction of pro-inflammatory cytokines and apoptotic biomarkers, increased red and white blood cell, platelet counts and abated pathological injuries in rat lungs treated with DOX alone. In essence, our findings indicate that LUT dose-dependently mitigated DOX-induced toxicities in the lungs and haematopoietic systems. Supplementation of patients on DOX-chemotherapy with phytochemicals exhibiting antioxidant activities, specifically LUT, could circumvent the onset of unintended toxic responses in the lungs and haematopoietic system exposed to DOX.

Introduction

Systemic administration of anticancer drugs is deleterious to dividing cells and is the integral approach for the treatment of malignant tumours (Afsar et al., 2019; Carvalho et al., 2009; Milic et al., 2009; Torres et al., 2010). Regrettably, most chemotherapeutic agents cannot efficiently distinguish between normal and malignant cells; thereby anticancer drugs non-selectively accumulates in healthy tissues causing severe clinical toxicities (Liao et al., 2018; Xu et al., 2018). The anthracycline antibiotic -Doxorubicin- (DOX) is one such drug, whose acute and chronic toxicities including that to lungs, haematopoietic cell -depressing the immune system by reducing immune cells- (Ahmed et al., 2019; Injac et al., 2009; Jacevic et al., 2018; Pugazhendhi et al., 2018; Tacar et al., 2013), and cardiotoxicity (Alhowail, 2020; Timm et al., 2020; Mohamed and Kassem, 2018; Imbaby et al., 2014) limit its clinical use. DOX intercalates with DNA and stalls topoisomerase II resulting in DNA double-strand breakages including mitochondrial DNA (Carvalho et al., 2009; Pang et al., 2013; Hilmer et al., 2004; Ashley and Poulton, 2009). DOX can easily target rapidly dividing cells, and inhibits cell growth in the G1 and G2 phase of the cell cycle (Tacar et al., 2013; Lucas et al., 2016). Bioactivation of DOX generates reactive oxygen and reactive nitrogen species (RONS) via semiquinone type of free radical reaction (Omobowale TO et al., 2018; McGowan et al., 2017; Molehin et al., 2019) that play a role in its toxicity. Furthermore, DOX overwhelms antioxidant enzyme activities, and total sulfhydryl levels ordinarily present in tissues (Milic et al., 2009; Mantawy et al., 2014). The perturbation in oxidant-antioxidant systems, in favours of the former, can result in lung injury through lipid peroxidation, the formation of protein cross-linking and DNA adducts (Srdjenovic et al., 2010; Vapa et al., 2012).

Studies have shown that lung and haematopoietic injuries, occasioned by toxic chemicals, are manifested through inflammatory processes alongside with increased free radical concentrations (Milic et al., 2009; Srdjenovic et al., 2010). Several lung and blood disorders, including those related to exposure to asbestos, benzene, phosgene as well as DOX (Gorguner and Akgun, 2010; Wani et al., 2015) are associated with RONS accumulation.

Various attempts to abate the toxic effect of DOX in the lungs and blood-forming tissues via dosage optimisation, synthesis and use of chemopreventive agents and their analogues have been reported (Injac et al., 2009). A number of these chemopreventive agents proved to be protective during DOX therapy (Carrasco et al., 2020; Qi et al., 2020; Tedesco et al., 2020). Luteolin (LUT), otherwise known as 2–3, [4-dihydroxyphenyl-5],7-dihydroxy-4-chromenone, is a member of the flavonoid family found in fruits and vegetables (Cook et al., 2016). LUT is studied extensively for its antioxidant properties (Tan et al., 2019; Xiao et al., 2019), and may act as a RONS scavenger in biological systems. In xenobiotics as well as irradiations-induced oxidative stress models, LUT has repeatedly shown protective effects against a wide range of cellular and tissue toxicants (Xiao et al., 2019; Kline, 2019; Kwon and Choi, 2018; Maneenet et al., 2019; Park and Song, 2019). In the present study, we examined the antioxidant levels, oxido-inflammatory, and apoptotic responses in the lungs and hematologic status of rats treated with DOX. Furthermore, we assessed the effect of LUT in abating DOX-induced biochemical and histological alterations in the lungs and blood functional parameters in rats co-administered with DOX. We found that LUT significantly mitigated the toxic changes occasioned by DOX alone treatment. To our knowledge, we report for the first time the effect of LUT abating DOX-mediated lung toxicity and altered haematological function.

Section snippets

Chemicals

LUT (>98 purity; CAS No: 491-70-3), DOX-hydrochloride (CAS No: 25316-40-9), epinephrine (CAS No: 329-63-5), glutathione (GSH; CAS No: 70-18-8), thiobarbituric acid (TBA; CAS No: 504-17-6), hydrogen peroxide (H2O2; CAS No: 7722-84-1), 5,5-dithio-bis-2-nitrobenzoic acid (DTNB; CAS No: 69-78-3), Griess reagent (CAS No: 1465-25-4), 1-chloro-2, 4-dinitrobenzene (CDNB; CAS No: 97-00-7), xanthine (CAS No:69-89-6), trichloroacetic acid (TCA; CAS No:76-03-9), and Bovine serum albumin (BSA; CAS

Administration of LUT enhanced survivability, mean body weight and organo-somatic indices in DOX-treated rats

We evaluated the protective role of LUT on DOX-toxicity to the lungs, we assessed rats body weight after for two weeks and the lungs weight at euthanasia. The results of survivability (Kaplan-Meyers), mean body weight, and relative lung weight are presented in Fig. 1 and Table 1. In comparison to the control, cohorts of rats treated with DOX alone exhibited a reduction in rats' survivability suggestive of DOX toxicity, while LUT (50 and 100 mg/kg) improved survival rats of rats in cohorts

Discussion

Toxicities associated with Doxorubicin limits its clinical use as a chemotherapeutic option against lungs malignancies (Srdjenovic et al., 2010; Vapa et al., 2012). Luteolin has demonstrates antioxidative, anti-inflammatory and anti-apoptotic functions in rat and human models (Cook et al., 2016; Park and Song, 2019; Yang et al., 2020). Consequently, we investigated the role of LUT on antioxidant, oxidative stress, inflammatory and apoptotic statuses in lung and haematologic function of rats

Authors contribution

All authors partook in the design, interpretation, analysis of the data generated from the study. SEO SON, OAO, AKO and UOA conceptualised the experiments; carried out the research and preliminary data analysis. SEO SON, OAO, AKO and UOA supervised the investigation. SEO SON, OAO, AKO and UOA checked the generated data for error. The manuscript was written and revised by SEO SON, OAO, AKO and UOA.

Funding

This research was done without a specific grant received from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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