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Antimetastatic pectic polysaccharide from Decalepis hamiltonii; galectin-3 inhibition and immune-modulation

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Abstract

Melanoma is a malignant neoplasm of major concern because of its high mortality rate and failure of chemotherapy. Previously we have shown that galectin-3, a galactose specific lectin, plays a pivotal role in the initiation of metastasis. It was hypothesized that blocking galectin-3 with galactose rich dietary pectic polymer would inhibit metastasis. The current study analyzes the preventive effect and mode of action of a pectic polymer from Swallow Root (Decalepis hamiltonii) in a preventative study of B16F10 cells lung colonization. Matrix metalloproteinase (MMPs) activity was assayed by zymography. Apoptotic/proliferative markers and cytokines were analyzed by immunoassay. Results indicated ~88% inhibition of lung colonization by SRPP as compared to 60% by CPP and only 7% by GRPP. Further molecular analysis revealed that galectin-3 blockade was associated with down regulation of MMPs and NFκB. Activation of caspases supported the apoptotic effect of SRPP. Infiltration of inflammatory cells into the lung was evidenced by presence of CD11b+ cells and release of the pro-inflammatory cytokine-IL-17, indicating inflammation during the cancer cell colonization process. SRPP enhanced the release of IL-12 that enables the reduction of inflammation. Our data for the first time indicate the effective anti-metastatic effect of SRPP due to both galectin-3 blockade and immunomodulation.

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Abbreviations

SRPP:

Swallow root pectic polysaccharide

GRPP:

Ginger pectic polysaccharide

CPP:

Citrus pectic polysaccharide

MMPs:

Matrixmetalloproteinase

References

  1. Goldsmith LA, Askin FB, Chang AE, Cohen C, Dutcher JP, Gilgor R, Swanson NA (1992) Diagnosis and treatment of early melanoma: NIH Consensus Development Panel on Early Melanoma. JAMA 268:1314–1319

    Article  Google Scholar 

  2. Chamelli J, Frances P, Noonan, Merlino G (2003) Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 22:3099–3112

    Article  Google Scholar 

  3. Friedmann PS, Gilchrest BA (1987) Ultraviolet radiation directly induces pigment production by cultured human melanocytes. J Cell Physiol 133:88–94

    Article  CAS  PubMed  Google Scholar 

  4. Kanavy HE, Gerstenblith MR (2011) Ultraviolet radiation and melanoma. Semin Cutan Med Surg 30:222–228

    Article  CAS  PubMed  Google Scholar 

  5. Hofmann UB, Westphal JR, Waas ET (1999) Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression. Br J Cancer 81:774–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Herrmann J, Truck CW, Atchison RE (1993) Primary structure of the soluble lactose binding lectin L-29 from rat and dog and interaction of its non-collagenous proline, glycine, tyrosine rich sequence with bacterial and tissue collagenase. J Biol Chem 208:26704–26711

    Google Scholar 

  7. Victor G, Prieto A, Alexandra (2006) Galectin-3 expression is associated with tumor progression and pattern of sun exposure in melanoma. Clin Cancer Res 12:6709–6715

    Article  Google Scholar 

  8. Sathisha UV, Smitha J, Harish Nayaka MA (2007) Inhibition of galectin-3 mediated cellular interactions by pectic polysaccharides from dietary sources. Glycoconj J 24:497–507

    Article  CAS  PubMed  Google Scholar 

  9. Raz A, Lotan R (1987) Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis. Cancer Metastasis Rev 6:433–452

    Article  CAS  PubMed  Google Scholar 

  10. Gao X, Zhi Y, Sun L, Peng X, Zhang T, Xue H, Tai G, Zhou Y (2013) The Inhibitory effects of a rhamnogalacturonan (RG-I) domain from ginseng pectin on galectin-3 and its structure-activity relationship. J Biol Chem 288:33953–33965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Inohara R, Raz A (1987) Effects of natural complex carbohydrate (citrus pectin) on murine melanoma cell properties related to galectin-3 functions. Glycoconj J 11:527–532

    Article  Google Scholar 

  12. Hansen MB, Nielsen SE, Berg K (1989) Reexamination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 119:203–210

    Article  CAS  PubMed  Google Scholar 

  13. Dubois M, Gilles KA, Hamilton JK, Rebers PA, Smith F (1956) Colorimetric method for determination of sugars and related substances. Anal Chem 28:350–356

    Article  CAS  Google Scholar 

  14. Cristina MC, Vicente VO, Josefa YM (2005) Treatment of metastastic melanoma B16F10 by the flavonoids tangeretin, rutin and diosmin. J Agric Food Chem 53:6791–6797

    Article  Google Scholar 

  15. Smitha Jayaram, Sabeeta Kapoor, Shylaja M Dharmesh (2015) Pectic polysaccharide from corn (Zea mays L.) effectively inhibited multistep mediated cancer cell growth and metastasis. Chem Biol Interact 235:63–75

    Article  CAS  PubMed  Google Scholar 

  16. Srikanta BM, Siddaraju MN, Shylaja M Dharmesh (2007) A novel phenol-bound pectic polysaccharide from Decalepis hamiltonii with multi-step ulcer preventive activity. World J Gastroenterol 13:5196–5207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Martinez C, Vicente V, Yanez M, Garcia JM, Canteras M, Alcaraz M (2005) Experimental model of pulmonary metastasis treatment with IFN alpha. Cancer Lett 225:75–83

    Article  CAS  PubMed  Google Scholar 

  18. Lentini A, Autuoria F, Mattiolia P, Caragliab M, Abbruzzeseb A, Beninati S (2000) Evaluation of the efficacy of potential antineoplastic drugs on tumour metastasis by a computer-assisted image analysis. Eur J Cancer 36:1572–1577

    Article  CAS  PubMed  Google Scholar 

  19. Brown ER, Doig T, Anderson N, Brenn T, Doherty V, Xu Y, Bartlett JM, Smyth JF, Melton DW (2012) Association of galectin-3 expression with melanoma progression and prognosis. Eur J Cancer 48:865–874

    Article  CAS  PubMed  Google Scholar 

  20. Balasubramanian K, Vasudevamurthy R, Sathisha UV (2009) Galectin-3 in urine of cancer patients: stage and tissue specificity. J Cancer Res Clin Oncol 135:355–363

    Article  CAS  PubMed  Google Scholar 

  21. Shiu-Chen H, Chi-Tang H, Shoei-Yn L (2005) Carnosol inhibits the invasion of B16F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun. Biochem Pharma 69:221–232

    Article  Google Scholar 

  22. Powell AA, LaRue JM Martinez JD (2001) Bile acid hydrophobicity is correlated with induction of apoptosis and/or growth arrest in HT 116 cells. Biochem J 356:481–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hibino S, Shibuya M, Engbring JA, Mochizuki M, Nomizu M, Kleinman HK (2004) Identification of an active site on the laminin alpha5 chain globular domain that binds to CD44 and inhibits malignancy. Cancer Res 64:4810–4816

    Article  CAS  PubMed  Google Scholar 

  24. Hosoi J, Abe E, Suda T (1985) Regulation of melanin synthesis of B16 mouse melanoma cells by 1 alpha, 25-dihydroxyvitamin D3 and retinoic acid. Cancer Res 45:1474–1478

    CAS  PubMed  Google Scholar 

  25. Siddaraju MN, Dharmesh SM (2006) A bioactive fraction from zingiber officinale and a process for the preparation thereof. US patent, US8158608

  26. Ochieng J, Fridman R, Nangia-Makker P (1994) Galectin-3 is a novel substrate for human matrix metalloproteinases-2 and -9. BioChemistry 33:14109–14114

    Article  CAS  PubMed  Google Scholar 

  27. Takenaka Y, Fukumori T, Yoshii T (2004) Nuclear export of phosphorylated galectin-3 regulates its anti-apoptotic activity in response to chemotherapeutic drugs. Mol Cell Biol 24:4395–4406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shathish K, Guruvayoorappan C (2014) Decalepis hamiltonii inhibits tumor progression and metastasis by regulating the inflammatory mediators and nuclear factor κB subunits. Integr Cancer Ther 13:141–151

    Article  PubMed  Google Scholar 

  29. Watson E (2013) Natural galectin-3 inhibitors from pectins are the next big thing in heart-healthy foods, says start-up. Breaking News on Food and Beverage Development, North America, 22 Mar 2013

  30. Azemar M, Hildenbrand B, Haering B, Heim ME, Unger C (2007) Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med Oncol 1:73–80

    CAS  Google Scholar 

  31. Pienta KJ, Naik H, Akhtar A et al (1995) Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87:348–353

    Article  CAS  PubMed  Google Scholar 

  32. Nangia-Makker P, Hogan V, Honjo Y et al (2002) Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Inst 94:1854–1862

    Article  CAS  PubMed  Google Scholar 

  33. Takenaka Y, Fukumori T, Raz A (2004) Galectin-3 and metastasis. Glycoconj J 19:543–549

    Article  PubMed  Google Scholar 

  34. Maxwell EG, Belshaw NJ, Waldron KW, Morris VJ (2012) Pectin-an emerging new bioactive food polysaccharide. Trends Food Sci Tech 24:64–73

    Article  CAS  Google Scholar 

  35. Redman JM, Gibney GT, Atkins MB (2016) Advances in immunotherapy for melanoma. BMC Med 14(1):1

    Article  Google Scholar 

  36. Zhang L, Wang P, Qin Y, Cong Q, Shao C, Du Z, Ni X, Li P, Ding K (2016) RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways. Oncogene. doi:10.1038/onc.2016.306

    Google Scholar 

  37. Menachem A, Bodner O, Pastor J, Raz A, Kloog Y (2015) Inhibition of malignant thyroid carcinoma cell proliferation by Ras and galectin-3 inhibitors. Cell Death Discov 1:15047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Platt D, Raz A (1992) Modulation of the lung colonization of B16-F1 melanoma cells by citrus pectin. J Nat Cancer Inst 84:438–442

    Article  CAS  PubMed  Google Scholar 

  39. Zhang T, Zheng Y, Zhao D, Yan J, Sun C, Zhou Y, Tai G (2016) Multiple approaches to assess pectin binding to galectin-3. Int J Biol Macromol 91:994–1001

    Article  CAS  PubMed  Google Scholar 

  40. Zhang T, Lan Y, Zheng Y, Liu F, Zhao D, Mayo KH, Zhou Y, Tai G (2016) Identification of the bioactive components from pH-modified citrus pectin and their inhibitory effects on galectin-3 function. Food Hydrocoll 58:113–119

    Article  CAS  Google Scholar 

  41. Liu FT, Rabinovich GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5:29–41

    Article  CAS  PubMed  Google Scholar 

  42. Kim K, Mayer EP, Nachtigal M (2003) Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. Biochim Biophys Acta (BBA) 1641(1):13–23

    Article  CAS  Google Scholar 

  43. Bugelski PJ, Kirsh RL, Sowinski JM, Poste G (1985) Changes in the macrophage content of lung metastases at different stages in tumor growth. Am J Pathol 118(3):419

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tugues S, Burkhard SH, Ohs I, Vrohlings M, Nussbaum K, Vom Berg J, Becher B (2015) New insights into IL-12-mediated tumor suppression. Cell Death Differ 22(2):237–246

    Article  CAS  PubMed  Google Scholar 

  46. Seder RA, Kelsall BL, Jankovic D (1996) Differential roles for IL-12 in the maintenance of immune responses in infectious versus autoimmune disease. J Immunol 157(7):2745–2748

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank the Director, CSIR-Central Food Technological Research Institute, for his keen interest in the work and encouragement. SMD is thankful to Department of Science and Technology and Department of Biotechnology, New Delhi for the financial assistance through projects. Dr. Mahadeva, Professor of English, University of Mysore, Mysore has been acknowledged for his kind support in English correction. UVS, SEM and HMA gracefully acknowledge the Senior Fellowships provided by Indian Council of Medical Research and Council of Scientific and Industrial Research, New Delhi, India, respectively.

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    1. Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysuru, 570 020, Karnataka, India

      Sathisha U. Venkateshaiah, Mallikarjuna S. Eswaraiah, Harish Nayaka M. Annaiah & Shylaja M. Dharmesh

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    1. Sathisha U. Venkateshaiah
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    Correspondence to Shylaja M. Dharmesh.

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    Sathisha U. Venkateshaiah and Mallikarjuna S. Eswaraiah are equal first authors.

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    Venkateshaiah, S.U., Eswaraiah, M.S., Annaiah, H.N.M. et al. Antimetastatic pectic polysaccharide from Decalepis hamiltonii; galectin-3 inhibition and immune-modulation. Clin Exp Metastasis 34, 141–154 (2017). https://doi.org/10.1007/s10585-017-9836-z

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