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Chemoprophylactic activity of nitazoxanide in experimental model of mammary gland carcinoma in rats

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Abstract

The current study focuses on the evaluation of the chemoprophylactic activity of nitazoxanide against the mammary gland carcinoma in experimental rats. The experimental protocol involves total 50 female Wistar albino rats of body weight 120–150 g, which were randomly categorized into five groups; Normal control (1% w/v carboxymethyl cellulose, p.o.); Toxic control (N-methyl-N-nitrosourea, MNU, 47 mg/kg i.v.); Standard (MNU, 47 mg/kg i.v. + tamoxifen, 1 mg/kg p.o.); Treatment 1 (MNU, 47 mg/kg i.v. + NTZ low-dose, 25 mg/kg p.o.); and Treatment 2 (MNU, 47 mg/kg, i.v. + NTZ high-dose, 50 mg/kg p.o.). The mammary gland carcinoma was induced by a single tail vein intravenous injection of MNU at a 47 mg/kg dose. Seven days after MNU administration, daily dosing of nitazoxanide and tamoxifen was initiated till 110th day in respective groups. The MNU toxicity was apparent with the altered electrocardiogram and heart rate variability, increased number of alveolar bud count, differentiation score, and upregulated antioxidant parameters. Nitazoxanide treatment restored the histological architecture in rats along with the reduction of alveolar buds and downregulation of oxidative stress markers as well as inflammatory markers. Therefore, nitazoxanide can be utilized as a potential chemoprophylactic agent against mammary gland carcinoma induced by MNU.

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References

  • Abaza H, El-Zayadi AR, Kabil SM, Rizk H (1998) Nitazoxanide in the treatment of patients with intestinal protozoan and helminthic infections: a report on 546 patients in egypt. Curr Therap Res 59(2):116–121

    Article  CAS  Google Scholar 

  • Al-Saeedan AS, Gautam V, Ansari MN, Singh M, Yadav RK, Rawat JK, Devi U, Gautam S, Roy S, Kaithwas G (2018) Revisiting the systemic lipopolysaccharide mediated neuroinflammation: appraising the effect of l-cysteine mediated hydrogen sulphide on it. Saudi Pharm J 26(4):520–527

    Article  PubMed  PubMed Central  Google Scholar 

  • Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB (1994) Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54(17):4614–4617

    CAS  PubMed  Google Scholar 

  • de Assis S, Warri A, Idalia Cruz M, Hilakivi-Clarke L (2010) Changes in mammary gland morphology and breast cancer risk in rats. J Vis Exp 44:2260

    Google Scholar 

  • Devi U, Singh M, Roy S, Gupta PS, Ansari MN, Saeedan AS, Kaithwas G (2019a) Activation of prolyl hydroxylase-2 for stabilization of mitochondrial stress along with simultaneous downregulation of HIF-1α/FASN in ER + breast cancer subtype. Cell Biochem Func 37(4):216–227

    Article  CAS  Google Scholar 

  • Devi U, Singh M, Roy S, Tripathi AC, Gupta PS, Saraf SK, Ansari MN, Saeedan AS, Kaithwas G (2019b) PHD-2 activation: a novel strategy to control HIF-1α and mitochondrial stress to modulate mammary gland pathophysiology in ER+ subtype. Naunyn Schmiedebergs Arch Pharmacol 392(10):1239–1256

    Article  CAS  PubMed  Google Scholar 

  • Di Santo N, Ehrisman J (2013) Research perspective: potential role of nitazoxanide in ovarian cancer treatment. Old drug, new purpose? Cancers (Basel) 5(3):1163–1176

    Article  CAS  Google Scholar 

  • Ding XZ, Tong WG, Adrian TE (2001) 12-Lipoxygenase metabolite 12(S)-HETE stimulates human pancreatic cancer cell proliferation via protein tyrosine phosphorylation and ERK activation. Int J cancer 94(5):630–636

    Article  CAS  PubMed  Google Scholar 

  • Fan-Minogue H, Bodapati S, Solow-Cordero D, Fan A, Paulmurugan R, Massoud TF, Felsher DW, Gambhir SS (2013) A c-Myc activation sensor-based high-throughput drug screening identifies an antineoplastic effect of nitazoxanide. Mol Cancer Ther 12(9):1896–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gautam R, Singh M, Gautam S, Rawat JK, Saraf SA, Kaithwas G (2016) Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects. BMC Complement Altern Med 16(99):1–6

    Google Scholar 

  • Gautam S, Rawat AK, Sammi SR, Roy S, Singh M, Devi U, Yadav RK, Singh L, Rawat JK, Ansari MN, Saeedan AS, Kumar D, Pandey R, Kaithwas G (2018a) DuCLOX-2/5 inhibition attenuates inflammatory response and induces mitochondrial apoptosis for mammary gland chemoprevention. Front Pharmacol 9(314):1–17

    Google Scholar 

  • Gautam S, Singh P, Singh M, Roy S, Rawat JK, Yadav RK, Devi U, Gupta PS, Saraf SA, Kaithwas G (2018b) Rifaximin, a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer. RSC Adv 8(7):3512–3521

    Article  CAS  Google Scholar 

  • Hemphill A, Mueller J, Esposino M (2006) Nitazoxanide, a broad-spectrum thiazolide anti-infective agent for the treatment of gastrointestinal infections. Expert Opin Pharmacother 7(7):953–964

    Article  CAS  PubMed  Google Scholar 

  • Hoffman PS, Sisson G, Croxen MA, Welch K, Harman WD, Cremades N, Morash MG (2007) Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrob Agents Chemother 51(3):868–876

    Article  CAS  PubMed  Google Scholar 

  • Hong SK, Kim HJ, Song CS, Choi IS, Lee JB, Park SY (2012) Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int Immunopharmacol 13(1):23–27

    Article  CAS  PubMed  Google Scholar 

  • Jagadeesan J, Nandakumar N, Rengarajan T, Balasubramanian MP (2012) Diosgenin, a steroidal saponin, exhibits anticancer activity by attenuating lipid peroxidation via enhancing antioxidant defense system during NMU induced breast carcinoma. J Environ Pathol Toxicol Oncol 31(2):121–129

    Article  CAS  PubMed  Google Scholar 

  • Lam KKY, Zheng X, Forestieri R, Balgi AD, Nodwell M, Vollett S, Anderson HJ, Anderson RJ, Av-Gay Y, Roberge M (2012) Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis. PLoS Pathog 8(5):e1002691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HH, Lim CA, Cheong YT, Singh M, Gam LH (2012) Comparison of protein expression profiles of different stages of lymph nodes metastasis in breast cancer. Int J biolsci 8(3):353–362

    Article  CAS  Google Scholar 

  • Lu W, Zhao X, Xu Z, Dong N, Zou S, Shen X, Huang J (2013) Development of a new colorimetric assay for lipoxygenase activity. Anal Biochem 441(2):162–168

    Article  CAS  PubMed  Google Scholar 

  • Mallikarjuna GU, DhanalakshmiS RS, Rao AR (2003) Chemomodulatory influence of Ferula asafoetida on mammary epithelial differentiation, hepatic drug metabolizing enzymes, antioxidant profiles and N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. Breast Cancer Res Treat 81(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • Manral C, Roy S, Singh M, Gautam S, Yadav RK, Rawat JK, Devi U, Ansari MN, Saeedan AS, Kaithwas G (2016) Effect of β-sitosterol against methyl nitrosourea-induced mammary gland carcinoma in albino rats. BMC Complementary Altern Med 16(1):1–10

    Article  CAS  Google Scholar 

  • Matsuyama M, Yoshimura R (2008) The target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer. Biologics 2(4):725–732

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra RK, Sammi SR, Rawat JK, Roy S, Singh M, Gautam S, Yadav RK, Devi U, Ansari MN, Saeedan AS, Saraf SA, Pandey R, Kaithwas G (2016) Palonosetron attenuates 1,2-dimethyl hydrazine induced preneoplastic colon damage through downregulating acetylcholinesterase expression and up-regulating synaptic acetylcholine concentration. RSC Adv 6(46):40527–40538

    Article  CAS  Google Scholar 

  • Müller-Decker K, Berger I, Ackermann K, Ehemann V, Zoubova S, Aulmann S, Pyerin W, Fürstenberger G (2005) Cystic duct dilatations and proliferative epithelial lesions in mouse mammary glands upon keratin 5 promoter-driven overexpression of cyclooxygenase-2. Am J Pathol 166(2):575–584

    Article  PubMed  PubMed Central  Google Scholar 

  • Nie D, Hillman GG, Geddes T, Tang K, Pierson C, GrignonD J, Honn KV (1998) Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth. Cancer Res 58(18):4047–4051

    CAS  PubMed  Google Scholar 

  • Płonka J, Latocha M, Kus̈mierz D, Zielińska A (2015) Expression of proapoptotic BAX and TP53 genes and antiapoptotic BCL-2 gene in MCF-7 and T-47D tumour cell cultures of the mammary gland after a photodynamic therapy with photolon. Adv Clin Exp Med 24(1):37–46

    Article  PubMed  Google Scholar 

  • Rani A, Roy S, Singh M, Devi U, Yadav RK, Gautam S, Rawat JK, Ansari MN, Saeedan AS, Prakash A, Kaithwas G (2016) α-Chymotrypsin regulates free fatty acids and UCHL-1 to ameliorate N-methyl nitrosourea induced mammary gland carcinoma in albino wistar rats. Inflammopharmacology 24(5):277–286

    Article  CAS  PubMed  Google Scholar 

  • Rani V, Gautam S, Rawat JK, Singh M, Devi U, Yadav RK, Roy S, Kaithwas G (2018) Effects of minocycline and doxycycline against terbutaline induced early postnatal autistic changes in albino rats. Physiol Behav 183:49–56

    Article  CAS  PubMed  Google Scholar 

  • Rawat JK, Roy S, Singh M, Guatam S, Yadav RK, Ansari MN, Aldossary SA, Saeedan AS, Kaithwas G (2019) Transcutaneous vagus nerve stimulation regulates the cholinergic anti-inflammatory pathway to counteract 1, 2-dimethylhydrazine induced colon carcinogenesis in albino wistar rats. Front Pharmacol 10(353):1–13

    Google Scholar 

  • Reznick AZ, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 233:357–363

    Article  CAS  PubMed  Google Scholar 

  • Romano M, Clária J (2003) Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 17(14):1986–1995

    Article  CAS  PubMed  Google Scholar 

  • Rossignol JF, Maisonneuve H, Cho YW (1984) Nitroimidazoles in the treatment of trichomoniasis, giardiasis, and amebiasis. Int J Clin Pharmacol Ther Toxicol 22(2):63–72

    CAS  PubMed  Google Scholar 

  • Rossignol JF, Ayoub A, Ayers MS (2001a) Treatment of diarrhea caused by cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 184(1):103–106

    Article  CAS  PubMed  Google Scholar 

  • Rossignol JF, Ayoub A, Ayers MS (2001b) Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect dis 184(3):381–384

    Article  CAS  PubMed  Google Scholar 

  • Roy S, Rawat AK, Sammi SR, Devi U, Singh M, Gautam S, Yadav RK, Rawat JK, Singh L, Ansari MN, Saeedan AS, Pandey R, Kumar D, Kaithwas G (2017) Alpha-linolenic acid stabilizes HIF-1 α and downregulates FASN to promote mitochondrial apoptosis for mammary gland chemoprevention. Oncotarget 8(41):70049–70071

    Article  PubMed  PubMed Central  Google Scholar 

  • Roy S, Singh M, Rawat A, Devi U, Gautam S, Yadav RK, Rawat JK, Ansari MN, Saeedan AS, Kumar D, Kaithwas G (2018) GLA supplementation regulates PHD2 mediated hypoxia and mitochondrial apoptosis in DMBA induced mammary gland carcinoma. Int J Biochem Cell Biol 96:51–62

    Article  CAS  PubMed  Google Scholar 

  • Roy S, Singh M, Rawat A, Kumar D, Kaithwas G (2019) ALA-mediated biphasic downregulation of α-7nAchR/HIF-1α along with mitochondrial stress modulation strategy in mammary gland chemoprevention. J Cell Physiol 234(4):4015–4029

    Article  CAS  PubMed  Google Scholar 

  • Senkowski W, Zhang X, Olofsson MH, Isacson R, Höglund U, Gustafsson M, Nygren P, Linder S, Larsson R, Fryknäs M (2015) Three-dimensional cell culture-based screening identifies the anthelmintic drug nitazoxanide as a candidate for treatment of colorectal cancer. Mol Cancer Ther 14(6):1504–1516

    Article  CAS  PubMed  Google Scholar 

  • Shen X, Pattillo CB, Pardue S, Bir SC, Wang R, Kevil CG (2011) Measurement of plasma hydrogen sulfide in vivo and in vitro. Free Radic Biol Med 50(9):1021–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh M, Devi U, Roy S, Gupta PS, Saraf SA, Kaithwas G (2016) Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma. Breast Cancer Free Radic Biol Med 50(9):1021–1031

    Google Scholar 

  • Singh M, Devi U, Roy S, Gupta PS, Kaithwas G (2018) Chemical activation of prolyl hydroxylase-2 by BBAP-1 down regulates hypoxia inducible factor-1α and fatty acid synthase for mammary gland chemoprevention. RSC Adv 8(23):12848–12860

    Article  CAS  Google Scholar 

  • Singh M, Kasna S, Roy S, Aldosary S, Saeedan AS, Ansari MN, Kaithwas G (2019) Repurposing mechanistic insight of PDE-5 inhibitor in cancer chemoprevention through mitochondrial-oxidative stress intervention and blockade of DuCLOX signalling. BMC Cancer 19(1):996

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sisson G, Goodwin A, Raudonikiene A, Hughes NJ, Mukhopadhyay AK, Berg DE, Hoffman PS (2002) Enzymes associated with reductive activation and action of nitazoxanide, nitrofurans, and metronidazole in Helicobacter pylori. Antimicrob Agents Chemother 46(7):2116–2123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stockis A, Deroubaix X, Lins R, Jeanbaptiste B, Calderon P, Rossignol JF (1996) Pharmacokinetics of nitazoxanide after single oral dose administration in 6 healthy volunteers. Int J Clin Pharmacol Ther 34(8):349–351

    CAS  PubMed  Google Scholar 

  • Stockis A, De Bruyn S, Gengler C, Rosillon D (2002) Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g bid. Int J Clin Pharmacol Ther 40(5):221–227

    Article  CAS  PubMed  Google Scholar 

  • Telo S, Halifeoglu I, Ozercan IH (2017) Effects of stinging nettle (Urtica dioica L.) on antioxidant enzyme activities in rat model of mammary gland cancer. Iran J Pharm Res 16(Suppl):164–170

    PubMed  PubMed Central  Google Scholar 

  • Tiwari V, Singh M, Rawat JK, Devi U, Yadav RK, Roy S, Gautam S, Saraf SA, Kumar V, Ansari N, Saeedan AS, Kaithwas G (2016) Redefining the role of peripheral LPS as a neuroinflammatory agent and evaluating the role of hydrogen sulphide through metformin intervention. Inflammopharmacology 24(5):253–264

    Article  CAS  PubMed  Google Scholar 

  • Wise R, Duhachek-Muggy S, Qi Y, Zolkiewski M, Zolkiewska A (2016) Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells. Breast Cancer Res Treat 157(2):241–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to express sincere thanks to Dr. Manjari Singh, Assistant Professor, Dept. of Pharmaceutical Sciences, Assam University, Silchar, India for her continuous scientific inputs and review.

Funding

This study was not supported by any funding agencies.

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Authors and Affiliations

  1. Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, Sector-3, MB Road, New Delhi, 110017, India

    Ajay Kumar Pal & Mukesh Nandave

  2. Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Rae Bareli Road, Lucknow, 226025, India

    Gaurav Kaithwas

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  1. Ajay Kumar Pal
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  2. Mukesh Nandave
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  3. Gaurav Kaithwas
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Contributions

AKP formulated the hypothesis, carried out bench work of the study and drafted the manuscript; MN carried out statistical analysis of the study and proofread the manuscript; GK supervised the work and proofread the manuscript.

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Correspondence to Ajay Kumar Pal.

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Authors have no conflict of interest.

Ethical approval

This study was approved by Institutional Animal Ethics Committee (IAEC) of Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, Uttar Pradesh, INDIA with approval no. IAEC/SHIATS/17MBM11.

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Pal, A.K., Nandave, M. & Kaithwas, G. Chemoprophylactic activity of nitazoxanide in experimental model of mammary gland carcinoma in rats. 3 Biotech 10, 338 (2020). https://doi.org/10.1007/s13205-020-02332-z

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