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Vanadium quercetin complex attenuates mammary cancer by regulating the P53, Akt/mTOR pathway and downregulates cellular proliferation correlated with increased apoptotic events

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Abstract

Flavonoid metal ion complexes have been deliberated in recent years and are considered as a new class of medicinal agents with enhanced therapeutic activity and low toxicity. Our study deals with chemotherapeutic effects of vanadium, when coordinated with the flavonoid quercetin on a defined model of chemically induced rat mammary carcinogenesis in vivo and on human breast cancer cell line MCF-7 in vitro. The characterization of the complex was achieved through UV–Visible, IR, and Mass spectra and antioxidant activity was assessed by DPPH, FRAP and ABTS methods. In vitro studies established that the complex upregulated the expressions of p53, Caspase 3 and 9, whereas down regulating Akt, mTOR and VEGF expressions and also induced apoptosis and DNA fragmentation in a dose dependent manner. Acute and Sub-acute toxicity was performed to determine safe doses. 7,12-Dimethylbenz(α)anthracene (0.5 mg/100 g body weight) was used for induction of breast cancer in female Sprague–Dawley rats via single tail vein injection. The histopathological analysis after 24 weeks of carcinogenesis study depicted substantial repair of hyperplastic lesions. TUNEL assay showed an increase in apoptotic index (0.14 ± 0.03; 0.15 ± 0.01) in vanadium–quercetin treated groups as compared to the carcinogen control (0.02 ± 0.01) along with upregulation of Bcl-2 and downregulation of Bax and p53. Immunohistochemical analysis also exhibited decrease in cell proliferation in the vanadium–quercetin treated groups (11.3 ± 0.12; 11.8 ± 0.10). Thus, results from both in vivo and in vitro studies revealed that vanadium–quercetin complex could be a potential candidate for development of approved drug for breast cancer in the near future.

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References

  • Advani SH (2010) Targeting mTOR pathway: a new concept in cancer therapy. Indian J Med Paediatr Oncol 31:132–136

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Badea M, Olar R, Marinescu D, Uivarosi V, Aldea V, Nicolescu TO (2010) Thermal stability of new vanadyl complexes with flavonoid derivatives as potential insulin-mimetic agents. J Therm Anal Calorim 99:823–827

    Article  CAS  Google Scholar 

  • Banerjee SK, Banerjee S (2012) CCNS/WISP-2: a micromanager of breast cancer progression. J Cell Commun Signal 6:63–71

    Article  PubMed  PubMed Central  Google Scholar 

  • Benzie IFF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239:70–76

    Article  PubMed  CAS  Google Scholar 

  • Currier N, Solomon SE, Demicco EG, Chang DL, Farago M, Ying H, Dominguez I, Sonenshein GE, Cardiff RD, Xiao ZX, Sherr DH, Seldin DC (2005) Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol Pathol 33:726–737

    Article  PubMed  CAS  Google Scholar 

  • Dehghan G, Khoshkam Z (2012) Tin (II)-quercetin complex: synthesis, spectral characterization and antioxidant activity. Food Chem 131:422–426

    Article  CAS  Google Scholar 

  • Deng XH, Song HY, Zhou YF, Yuan GY, Zheng FJ (2013) Effects of quercetin on the proliferation of breast cancer cells and expression of survivin in vitro. Exp Ther Med 6:1155–1158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ferlay J, Soerjomataram I, Dishit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCON 2012. Int J Cancer 136:E359–E386

    Article  PubMed  CAS  Google Scholar 

  • Ferrer EG, Salinas MV, Correa MJ, Naso L, Barrio DA, Etcheverry SB, Lezama L, Rojo T, Williams PAM (2006) Synthesis, characterization, antitumoral and osteogenic activities of quercetin vanadyl(IV) complexes. J Biol Inorg Chem 11:791–801

    Article  PubMed  CAS  Google Scholar 

  • Francipane MG, Lagasse E (2013) mTOR pathway in colorectal cancer: an update. Oncotarget 1:49–66

    Google Scholar 

  • Frezza M, Hindo S, Chen D, Davenport A, Schmitt S, Tomco D, Dou QP (2010) Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des 16:1813–1825

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fridman JS, Lowe SW (2003) Control of apoptosis by p53. Oncogene 22:9030–9040

    Article  PubMed  CAS  Google Scholar 

  • Ghoncheh M, Momenimovahed Z, Salehiniya H (2016) Epidemiology, incidence and mortality of breast cancer in Asia. Asian Pac J Cancer Prev 17:47–52

    Article  PubMed  Google Scholar 

  • Grazul M, Budzisz E (2009) Biological activity of metal ions complexes of chromones, coumarins and flavones. Coordin Chem Rev 253:2588–2598

    Article  CAS  Google Scholar 

  • Hassan M, Watari H, Abualmatty A, Ohba Y, Sakuraqi N (2014) Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014:150845

    PubMed  PubMed Central  Google Scholar 

  • Kanakis CD, Tarantilis PA, Polissiou MG, Diamantoglou S, Tajmir-Riahi HA (2007) An overview of DNA and RNA bindings to antioxidant flavonoids. Cell Biochem Biophys 49:29–36

    Article  PubMed  CAS  Google Scholar 

  • Kirubha SPA, Anburajan M, Venkataraman RA, Akila R, Sharath D, Baldev R (2012) Evaluation of mammary cancer in 7,12-dimethylbenz(α)anthracene-induced Wistar rats by asymmetrical temperature distribution analysis using thermography: a Comparison with serum CEA levels and histopathology. J Biomed Biotech 2012:786417

    Google Scholar 

  • Leon IE, Diez P, Etcheverry SB, Fuentes M (2016) Deciphering the effect of an oxovanadium(IV) complex with the flavonoid chrysin (VOChrys) on intracellular cell signaling pathways in an osteosarcoma cell line. Metallomics 8:739

    Article  PubMed  CAS  Google Scholar 

  • Miyata M, Furukawa M, Takahashi K, Gonzalez FJ, Yamazoe Y (2001) Mechanism of 7, 12-dimethylbenzanthracene induced immunotoxicity: role of metabolic activation at the target organ. Jap J Pharmacol 86:302–309

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee B, Patra B, Mahapatra S, Banerjee P, Tiwari A, Chatterjee M (2004) Vanadium—an element of atypical biological significance. J Toxicol Lett 150:135–143

    Article  CAS  Google Scholar 

  • Musualik M, Kuzmicz R, Pawlowski TS, Litwinienko G (2009) Acidity of hydroxyl groups: an overlooked influence on antiradical properties of flavonoids. J Org Chem 79:2699–2709

    Article  CAS  Google Scholar 

  • Muthurajan T, Rammanohar P, Rajendran NP, Sethuraman S, Krishnan UM (2015) Evaluation of a quercetin–gadolinium complex as an efficient positive contrast enhancer for magnetic resonance imaging. RSC Adv 5:86967–86979

    Article  CAS  Google Scholar 

  • Naso L, Valcarcel M, Villacé P, Ferrer MR, Salado C, Ferrera EG, Williams PAM (2014) Specific antitumor activities of natural and oxovanadium(IV) complexed flavonoids in human breast cancer cells. New J Chem 38:2414

    Article  CAS  Google Scholar 

  • Oliveria PA, Colaco A, Chaves R, Pinto HG, La-Cruz LF, Lopez C (2007) Chemical carcinogenesis. Ann Braz Acad Sci 79:593–616

    Article  Google Scholar 

  • Organization for Economic Co-operation and Development (OECD) for Testing of Chemicals, India (2001). http://www.oecd.org/chemicalsafety/risk-assessment/1948378.pdf/

  • Pennycooke JC, Cox S, Stushnoff JC (2005) Relationship of cold acclimation, total phenolic content and antioxidant capacity with chilling tolerance in petunia (Petunia × hybrida). Environ Exp Bot 53:225–232

    Article  CAS  Google Scholar 

  • Plati J, Bucur O, Khosravi-Far R (2008) Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biocem 104:1124–1149

    Article  CAS  Google Scholar 

  • Purushothaman A, Nandhakumar E, Sachdanandam P (2012) Anticancer effect of shemamruthaa (a phytochemical formulation) on 7, 12-dimethylbenz(α)anthracene induced mammary carcinoma in rats. Asian J Pharm Clin Res 5:101–107

    Google Scholar 

  • Rafique S, Idrees M, Nasim A, Akbar H (2010) Transition metal complexes as potential therapeutic agents. Biotechnol Mol Biol Rev 5:38–45

    CAS  Google Scholar 

  • Ranganathan S, Halagowder D, Sivasithambaram DN (2015) Quercetin suppresses twist to induce apoptosis in MCF-7 breast cancer cells. PLoS ONE 10:10

    Article  CAS  Google Scholar 

  • Ray RS, Roy S, Ghosh S, Kumar M, Chatterjee M (2004) Suppression of cell proliferation, DNA protein cross-links, and induction of apoptosis by vanadium in chemical rat mammary carcinogenesis. Biochem Biophys Acta 1675:165–173

    Article  CAS  Google Scholar 

  • Ray RS, Ghosh B, Rana A, Chatterjee M (2006) Suppression of cell proliferation, induction of apoptosis and cell cycle arrest: chemotherapeutic activity of vanadium in vivo and in vitro. Int J Cancer 120:13–23

    Article  CAS  Google Scholar 

  • Reddy SR, Parthasarathy N, Chidambaram N, Kumar AP (2012) Quercetin in dimethyl benzanthracene induced breast cancer in rats. Am J Pharmacol Toxicol 7:68–72

    Article  CAS  Google Scholar 

  • Roy S, Ahmed F, Banerjee S, Saha U (2016) Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-β1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events. Pharm Biol 54:1616–1627

    Article  PubMed  CAS  Google Scholar 

  • Samy RP, Gopalakrishnakone P, Ignacimuthu S (2006) Anti-tumor promoting potential of luteolin against 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats. Chemico Biol Int 164:1–14

    Article  CAS  Google Scholar 

  • Sanna D, Ugone V, Fadda A, Micera G, Garribba E (2016) Behavior of the potential antitumor VIVO complexes formed by flavonoid ligands. 3. Antioxidant properties and radical production capability. J Inorg Biochem S0162–0134(16):30113-1

    Google Scholar 

  • Selvaraj K, Chowdhury R, Bhattacharjee C (2013) Isolation and structural elucidation of flavonoids from aquatic fern Azolla microphylla and evaluation of free radical scavenging activity. Int J Pharm Pharm Sci 01:743–749

    Google Scholar 

  • Shukla R, Barve V, Padhye S, Bhonde R (2004) Synthesis, structural properties and insulin-enhancing potential of bis(quercetinato)oxovanadium(IV) conjugate. Bioorg Med Chem Lett 14:4961–4965

    Article  PubMed  CAS  Google Scholar 

  • Shukla R, Barve V, Padhye S, Bhonde R (2006) Reduction of oxidative stress induced vanadium toxicity by complexing with a flavonoid, quercetin: a pragmatic therapeutic approach for diabetes. Biometals 19:685–693

    Article  PubMed  CAS  Google Scholar 

  • Stevens JJ, Evans BG, Walker AM, Armstead B, Tchounwou PB (2008) Cytotoxic effect of arsenic trioxide in adenocarcinoma colorectal cancer (HT-29) cells. Met Ions Biol Med 10:458–462

    PubMed  PubMed Central  Google Scholar 

  • Symonowicz M, Kolanek M (2012) Flavonoids and their properties to form chelate complexes. Biotechnol Food Sci 76:35–41

    CAS  Google Scholar 

  • Tirona MT, Sehgal R, Balleste O (2010) Prevention of breast cancer (Part-I): epidemiology, risk factors and risk assessment tools. Cancer Investig 28:743–750

    Article  Google Scholar 

  • Tu LY, Pi J, Jin H, Cai JY, Deng SP (2016) Synthesis, characterization and anticancer activity of kaempferol-zinc(II) complex. Bioorg Med Chem 26:2730–2734

    Article  CAS  Google Scholar 

  • Uivarosi V, Barbuceanu SF, Aldea V, Arama CC, Badea M, Olar R, Marinescu D (2010) Synthesis, spectral and thermal studies of new rutin vanadyl complexes. Molecules 15:1578–1589

    Article  PubMed  CAS  Google Scholar 

  • Warra AA (2011) Transition metal complexes and their application in drugs and cosmetics—a review. J Chem Pharm Res 3:951–958

    CAS  Google Scholar 

  • Witty JP, Lempka T, Coffey RJ Jr, Matrisian LM (1995) Decreased tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res 55:1401–1406

    PubMed  CAS  Google Scholar 

  • Zhuo Z, Hu J, Yang X, Chen M, Lei X, Deng L, Yao N, Peng Q, Chen Z, Ye W, Zhang D (2015) Ailanthone inhibits Huh7 cancer cell growth via cell cycle arrest and apoptosis in vitro and in vivo. Sci Rep 5:16185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgement

The authors are highly obliged to Haricharan Garg charitable trust for their financial support in this research work. The authors would also like to thank Mr. Lal Mohan Masanta and Mr. Pravanjan Bhakta for their support.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, NSHM Knowledge Campus, 124 B.L. Saha Road, Kolkata, West Bengal, 700053, India

    Souvik Roy & Tania Chakraborty

  2. Syngene International Limited, Velankani Tech Park, Electronic city, Phase 1, Housar Road, Bangalore, Karnataka, 560100, India

    Sritama Banerjee

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  1. Souvik Roy
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Correspondence to Souvik Roy.

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Roy, S., Banerjee, S. & Chakraborty, T. Vanadium quercetin complex attenuates mammary cancer by regulating the P53, Akt/mTOR pathway and downregulates cellular proliferation correlated with increased apoptotic events. Biometals 31, 647–671 (2018). https://doi.org/10.1007/s10534-018-0117-3

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