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Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line

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Abstract

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request.

References

  • Abusara OH, Ibrahim AIM, Issa H, Hammad AM, Ismail WH (2023) In Vitro evaluation of ALDH1A3-Affinic compounds on breast and prostate Cancer cell lines as single treatments and in combination with Doxorubicin. Curr Issues Mol Biol 45:2170–2181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Ali L, Al-Ani RJ, Saleh MM, Hammad AM, Abuarqoub DA, Abu-Irmaileh B, Naser AY, Najdawi MM, Abbas MM, Alyoussef Alkrad J (2024) Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia. Saudi Pharm J 32:101931

    Article  CAS  PubMed  Google Scholar 

  • Appelbaum PC, Hunter PA (2000) The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents 16:5–15

    Article  CAS  PubMed  Google Scholar 

  • Azhari S, Xu YS, Jiang QX, **a WS (2014) Physicochemical properties and chemical composition of Seinat (Cucumis melo var. Tibish) seed oil and its antioxidant activity. Grasas Aceites 65:e008

    Article  Google Scholar 

  • Bartlett JG, Dowell SF, Mandell LA, File TM Jr., Musher DM, Fine MJ (2000) Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Diseases: Official Publication Infect Dis Soc Am 31:347–382

    Article  CAS  Google Scholar 

  • Brand-Williams W, Cuvelier ME, Berset C (1995) Use of a free radical method to evaluate antioxidant activity. LWT - Food Sci Technol 28:25–30

    Article  CAS  Google Scholar 

  • Caritá AC, Fonseca-Santos B, Shultz JD, Michniak-Kohn B, Chorilli M, Leonardi GR (2020) Vitamin C: one compound, several uses. Advances for delivery, efficiency and stability. Nanomedicine: Nanatechnol Biology Med 24:102117

    Article  Google Scholar 

  • Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  CAS  PubMed  Google Scholar 

  • El-Demerdash FM, Ahmed MM, Baghdadi HH (2023) Punica granatum peel extract modulates levofloxacin-induced oxidative stress and testicular damage in rats. Tissue Cell 85:102227

    Article  CAS  PubMed  Google Scholar 

  • El-Malah A, Youssef A, Ismail M, Kamel M, Mahmoud Z (2021) New promising levofloxacin derivatives: design, synthesis, cytotoxic activity screening, Topo2β polymerase inhibition assay, cell cycle apoptosis profile analysis. Bioorg Chem 113:105029

    Article  CAS  PubMed  Google Scholar 

  • Fan F, Yin R, Wang L, Zhao S, Lv D, Yang K, Geng S, Yang N, Zhang X, Wang H (2021) ALDH3A1 driving tumor metastasis is mediated by p53/BAG1 in lung adenocarcinoma. J Cancer 12:4780–4790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng H, Liu Y, Bian X, Zhou F, Liu Y (2018) ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status. Br J Cancer 118:224–232

    Article  CAS  PubMed  Google Scholar 

  • Fisusi FA, Akala EO (2019) Drug combinations in breast Cancer therapy. Pharm Nanatechnol 7:3–23

    Article  CAS  Google Scholar 

  • Gao F, Zhou B, Xu JC, Gao X, Li SX, Zhu GC, Zhang XG, Yang C (2015) The role of LGR5 and ALDH1A1 in non-small cell lung cancer: Cancer progression and prognosis. Biochem Biophys Res Commun 462:91–98

    Article  CAS  PubMed  Google Scholar 

  • Haitham Abusara O, Freeman S, Aojula HS (2017) Pentapeptides for the treatment of small cell lung cancer: optimisation by N(ind)-alkyl modification of the tryptophan side chain. Eur J Med Chem 137:221–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanušová V, Boušová I, Skálová L (2011) Possibilities to increase the effectiveness of doxorubicin in cancer cells killing. Drug Metab Rev 43:540–557

    Article  PubMed  Google Scholar 

  • Hariono M, Rollando R, Yoga I, Harjono A, Suryodanindro A, Yanuar M, Gonzaga T, Parabang Z, Hariyono P, Febriansah R, Hermawansyah A, Setyani W, Wahab H (2021) Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study (Part II). Molecules (Basel, Switzerland), 26

  • He X, Yao Q, Fan D, You Y, Lian W, Zhou Z, Duan L (2022) Combination of levofloxacin and cisplatin enhances anticancer efficacy via co-regulation of eight cancer-associated genes. Discover Oncol 13:76

    Article  CAS  Google Scholar 

  • Hooper DC (2000) New uses for new and old quinolones and the challenge of resistance. Clin Infect Diseases: Official Publication Infect Dis Soc Am 30:243–254

    Article  CAS  Google Scholar 

  • Ibrahim AIM, Abul-Futouh H, Bourghli LMS, Abu-Sini M, Sunoqrot S, Ikhmais B, Jha V, Sarayrah Q, Abulebdah DH, Ismail WH (2022) Design and synthesis of Thionated Levofloxacin: insights into a New Generation of quinolones with potential therapeutic and Analytical Applications. Curr Issues Mol Biol 44:4626–4638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikhmais BA, Hammad AM, Abusara OH, Hamadneh L, Abumansour H, Abdallah QM, Ibrahim AIM, Elsalem L, Awad M, Alshehada R (2023) Investigating Carvedilol’s repurposing for the treatment of Non-small Cell Lung Cancer via Aldehyde dehydrogenase activity modulation in the Presence of β-Adrenergic agonists. Curr Issues Mol Biol 45:7996–8012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ismail WH, Abusara OH, Ikhmais B, Abul-Futouh H, Sunoqrot S, Ibrahim AIM (2023) Design, synthesis, and Biological Activity of Coniferyl Aldehyde Derivatives as potential anticancer and antioxidant agents. Jordan J Pharm Sci 16:368–380

    Article  Google Scholar 

  • Jawad B, Poudel L, Podgornik R, Steinmetz NF, Ching WY (2019) Molecular mechanism and binding free energy of doxorubicin intercalation in DNA. Phys Chem Chem Phys 21:3877–3893

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Li H, Wang Y, Tian T, He Y, ** Y, Han C, ** X, Zhang F, Morii E (2017) ALDH enzyme activity is regulated by Nodal and histamine in the A549 cell line. Oncol Lett 14:6955–6961

    PubMed  PubMed Central  Google Scholar 

  • Kahlert C, Gaitzsch E, Steinert G, Mogler C, Herpel E, Hoffmeister M, Jansen L, Benner A, Brenner H, Chang-Claude J, Rahbari N, Schmidt T, Klupp F, Grabe N, Lahrmann B, Koch M, Halama N, Büchler M, Weitz J (2012) Expression analysis of aldehyde dehydrogenase 1A1 (ALDH1A1) in colon and rectal cancer in association with prognosis and response to chemotherapy. Ann Surg Oncol 19:4193–4201

    Article  PubMed  Google Scholar 

  • Khan AM, Rampal S, Sood NK (2017) Effect of repeated oral administration of levofloxacin, enrofloxacin, and meloxicam on antioxidant parameters and lipid peroxidation in rabbits. Hum Exp Toxicol 36:42–50

    Article  CAS  PubMed  Google Scholar 

  • Kim IG, Kim SY, Choi SI, Lee JH, Kim KC, Cho EW (2014) Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH + lung cancer stem cells through IGF1R signaling. Oncogene 33:3908–3917

    Article  CAS  PubMed  Google Scholar 

  • Kloskowski T, Szeliski K, Fekner Z, Rasmus M, Dąbrowski P, Wolska A, Siedlecka N, Adamowicz J, Drewa T, Pokrywczyńska M (2021) Ciprofloxacin and levofloxacin as potential drugs in Genitourinary Cancer Treatment-The Effect of dose-response on 2D and 3D cell cultures. Int J Mol Sci, 22

  • Koch A, Tamez P, Pezzuto J, Soejarto D (2005) Evaluation of plants used for antimalarial treatment by the Maasai of Kenya. J Ethnopharmacol 101:95–99

    Article  CAS  PubMed  Google Scholar 

  • Legnani L, Toma L, Caramella P, Chiacchio MA, Giofrè S, Delso I, Tejero T, Merino P (2016) Computational mechanistic study of Thionation of Carbonyl compounds with Lawesson’s reagent. J Org Chem 81:7733–7740

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Huang X, Shi F, Song J, Guo C, Yang J, Liang T, Bai X (2022) Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy. J Experimental Clin cancer Research: CR 41:56

    Article  CAS  PubMed Central  Google Scholar 

  • Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, Helyer L, Pan L, Leidal A, Gujar S, Giacomantonio CA, Lee PW (2011) Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells 29:32–45

    Article  CAS  PubMed  Google Scholar 

  • McGregor JC, Allen GP, Bearden DT (2008) Levofloxacin in the treatment of complicated urinary tract infections and acute pyelonephritis. Ther Clin Risk Manag 4:843–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moiseeva AA (2019) Anthracycline derivatives and their anticancer activity. J Nesmeyanov Inst Organoelement Compd Russian Acad Sci 2:9–18

    CAS  Google Scholar 

  • Mondal ER, Das SK, Mukherjee P (2004) Comparative evaluation of antiproliferative activity and induction of apoptosis by some fluoroquinolones with a human non-small cell lung cancer cell line in culture. Asian Pac J cancer Prevention: APJCP 5:196–204

    CAS  Google Scholar 

  • Moreb JS, Baker HV, Chang LJ, Amaya M, Lopez MC, Ostmark B, Chou W (2008) ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells. Mol Cancer 7:87

    Article  PubMed  PubMed Central  Google Scholar 

  • Muzio G, Maggiora M, Paiuzzi E, Oraldi M, Canuto RA (2012) Aldehyde dehydrogenases and cell proliferation. Free Radic Biol Med 52:735–746

    Article  CAS  PubMed  Google Scholar 

  • Nickel JC, Downey J, Clark J, Casey RW, Pommerville PJ, Barkin J, Steinhoff G, Brock G, Patrick AB, Flax S, Goldfarb B, Palmer BW, Zadra J (2003) Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial. Urology 62:614–617

    Article  PubMed  Google Scholar 

  • Noguchi N, Saito Y, Niki E (2023) Actions of Thiols, Persulfides, and Polysulfides as Free Radical Scavenging antioxidants. Antioxid Redox Signal 39:728–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • PDB (2024) RCSB Protein Data Bank. https://www.rcsb.org/

  • Russo JE, Hauguitz D, Hilton J (1988) Inhibition of mouse cytosolic aldehyde dehydrogenase by 4-(diethylamino)benzaldehyde. Biochem Pharmacol 37:1639–1642

    Article  CAS  PubMed  Google Scholar 

  • Sabbah DA, Haroon RA, Bardaweel SK, Hajjo R, Sweidan K (2020) N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: molecular docking, synthesis, and Biological Investigation as Anticancer agents. Molecules, 26

  • Singh S, Arcaroli J, Chen Y, Thompson DC, Messersmith W, Jimeno A, Vasiliou V (2015) ALDH1B1 is crucial for Colon tumorigenesis by modulating Wnt/β-Catenin, notch and PI3K/Akt signaling pathways. PLoS ONE 10:e0121648

    Article  PubMed  PubMed Central  Google Scholar 

  • Sissi C, Palumbo M (2003) The quinolone family: from antibacterial to anticancer agents. Curr Med Chem Anti-cancer Agents 3:439–450

    Article  CAS  PubMed  Google Scholar 

  • Song M, Wu H, Wu S, Ge T, Wang G, Zhou Y, Sheng S, Jiang J (2016) Antibiotic drug levofloxacin inhibits proliferation and induces apoptosis of lung cancer cells through inducing mitochondrial dysfunction and oxidative damage. Biomed Pharmacotherapy = Biomedecine Pharmacotherapie 84:1137–1143

    Article  CAS  PubMed  Google Scholar 

  • Storms RW, Trujillo AP, Springer JB, Shah L, Colvin OM, Ludeman SM, Smith C (1999) Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci USA 96:9118–9123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun JP, Shi ZY, Liu SM, Kang YH, Hu GQ, Huangfu CS, Deng JB, Liu B (2013) Trimethoxy-Benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells. Cancer Cell Int 13:67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sunoqrot S, Abusulieh S, Abusara OH (2023) Identifying synergistic combinations of doxorubicin-loaded polyquercetin nanoparticles and natural products: implications for breast cancer therapy. Int J Pharm 645:123392

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Tomita H, Hisamatsu K, Nakashima T, Hatano Y, Sasaki Y, Osada S, Tanaka T, Miyazaki T, Yoshida K, Hara A (2015) ALDH1A1-overexpressing cells are differentiated cells but not cancer stem or progenitor cells in human hepatocellular carcinoma. Oncotarget 6:24722–24732

    Article  PubMed  PubMed Central  Google Scholar 

  • Ulrich K, Jakob U (2019) The role of thiols in antioxidant systems. Free Radic Biol Med 140:14–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Pelger RC, van der Pluijm G (2011) The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis. Clin Exp Metastasis 28:615–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vasiliou V, Pappa A, Estey T (2004) Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism. Drug Metab Rev 36:279–299

    Article  CAS  PubMed  Google Scholar 

  • Wu L, Leng D, Cun D, Foged C, Yang M (2017) Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens. J Controlled Release: Official J Controlled Release Soc 260:78–91

    Article  CAS  Google Scholar 

  • Xu Y, Hu J, Zhu Q, Song Q, Mu Y (2018) Co-detection of ALDH1A1, ABCG2, ALCAM and CD133 in three A549 subpopulations at the single cell level by one-step digital RT-PCR. Integr Biology: Quant Biosci nano Macro 10:364–369

    Article  CAS  Google Scholar 

  • Yang SD, Bai ZL, Zhang F, Ma L, Yang DL, Ding WY (2014) Levofloxacin increases the effect of serum deprivation on anoikis of rat nucleus pulposus cells via Bax/Bcl-2/caspase-3 pathway. Toxicol Mech Methods 24:688–696

    Article  CAS  PubMed  Google Scholar 

  • Yu M, Li R, Zhang J (2016) Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer. Biochem Biophys Res Commun 471:639–645

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Al-Zaytoonah University of Jordan for financially supporting this work; fully supported by grant number 23/16/2021–2022 and partially supported by grant number 32/11/2020–2021.

Funding

This work was supported by Al-Zaytoonah University of Jordan grants; fully supported by grant number 23/16/2021–2022 and partially supported by grant number 32/11/2020–2021.

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Author notes

  1. Hamza Abumansour and Osama H. Abusara contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman, 11733, Jordan

    Hamza Abumansour, Osama H. Abusara, Ali I. M. Ibrahim, Mohammad K. Harb, Dina H. Abulebdah & Worood H. Ismail

  2. Department of Pharmacology, School of Medicine, The University of Jordan, Amman, 11942, Jordan

    Wiam Khalil

  3. Department of Chemistry, Faculty of Science, The Hashemite University, P.O. Box 330127, Zarqa, 13133, Jordan

    Hassan Abul-Futouh

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  1. Hamza Abumansour
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Contributions

Conceptualization: H.A. and O.H.A.; Methodology: H.A., O.H.A., W.K., H.A., A.I.M.I., M.K.H., D.H.A. and W.H.I.; Formal analysis and investigation: H.A. and O.H.A.; Writing - original draft preparation: H.A. and O.H.A.; Writing - review and editing: H.A., O.H.A., W.K., H.A. and A.I.M.I.; Funding acquisition: H.A. and O.H.A.; Supervision: H.A. and O.H.A. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Hamza Abumansour.

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Abumansour, H., Abusara, O.H., Khalil, W. et al. Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03075-x

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