Tumor Biology

, Volume 34, Issue 3, pp 1595–1603 | Cite as

Cisplatin and 4-hexylresorcinol synergise to decrease metastasis and increase survival rate in an oral mucosal melanoma xenograft model: a preliminary study

  • Sang-Woon Lee
  • Seong-Gon Kim
  • Young-Wook Park
  • HaeYong Kweon
  • Jwa-Young Kim
  • Horatiu Rotaru
Research Article


The present study was undertaken to examine the effects of cisplatin plus 4-hexylresorcinol (4-HR) combination therapy on oral mucosal melanoma (OMM) using cultured primary OMM cells in a tumour xenograft model. Cultured primary OMM cells were used for the MTT assay and DNA microarray. OMM cells were implanted into the submandibular glands of nude mice. The mice were then treated with cisplatin only or cisplatin plus 4-HR. Tumour size changes, survival rate and tumour metastasis were compared between the two groups by observation, micro-positron emission tomography (PET) and histological examination. In the MTT assay, the cisplatin plus 4-HR group showed significantly higher inhibition of OMM cell growth compared to the other groups (p < 0.05). DNA microarray results showed significant inhibition of matrix metalloproteinase (MMP)-2 gene expression upon 4-HR application. The necropsy and micro-PET results showed that the mice from the cisplatin-only group had more distant metastases than the mice from the cisplatin plus 4-HR combination group (p = 0.002). MMP-2 expression was lower in the primary tumours in the cisplatin plus 4-HR combination group than in the cisplatin-only group (p < 0.001). Overall survival was longer in mice from the cisplatin plus 4-HR combination group than in the cisplatin-only group (p = 0.049). In conclusion, the combined effect of cisplatin and 4-HR resulted in fewer metastases and longer survival than cisplatin-only treatment in the OMM xenograft model.


4-hexylresorcinol Oral mucosal melanoma Cisplatin Matrix metalloproteinases-2 



This work was supported by a grant from the Next-Generation BioGreen21 Program (No. PJ009013), Rural Development Administration, Republic of Korea.


  1. 1.
    Rapini RP, Golitz LE, Greer RO, et al. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer. 1985;55:1543–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncol. 2000;36:152–69.PubMedCrossRefGoogle Scholar
  3. 3.
    Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83:1664–78.PubMedCrossRefGoogle Scholar
  4. 4.
    Tanaka N, Mimura M, Ogi K, et al. Primary malignant melanoma of the oral cavity: assessment of outcome from the clinical records of 35 patients. Int J Oral Maxillofac Surg. 2004;33:761–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Barker BF, Carpenter WM, Daniels TE, et al. Oral mucosal melanomas: the WESTOP Banff workshop proceedings. Western Society of Teachers of Oral Pathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:672–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Umeda M, Komatsubara H, Shigeta T, et al. Treatment and prognosis of malignant melanoma of the oral cavity: preoperative surgical procedure increases risk of distant metastasis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:51–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Mücke T, Hölzle F, Kesting MR, et al. Tumor size and depth in primary malignant melanoma in the oral cavity influences survival. J Oral Maxillofac Surg. 2009;67:1409–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Lopez-Graniel CM, Ochoa-Carrillo FJ, Meneses-García A. Malignant melanoma of the oral cavity: diagnosis and treatment experience in a Mexican population. Oral Oncol. 1999;35:425–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Yang X, Ren GX, Zhang CP, et al. Neck dissection and post-operative chemotherapy with dimethyl triazeno imidazole carboxamide and cisplatin protocol are useful for oral mucosal melanoma. BMC Cancer. 2010;10:623.PubMedCrossRefGoogle Scholar
  10. 10.
    Umeda M, Shimada K. Primary malignant melanoma of the oral cavity—its histological classification and treatment. Br J Oral Maxillofac Surg. 1994;32:39–47.PubMedCrossRefGoogle Scholar
  11. 11.
    Vikey AK, Vikey D. Primary malignant melanoma, of head and neck: a comprehensive review of literature. Oral Oncol. 2012;48:399–403.PubMedCrossRefGoogle Scholar
  12. 12.
    Kruse AL, Riener MO, Graetz KW, et al. Mucosal malignant melanomas in head and neck surgery: a retrospective study of six patients and review of the literature. Oral Maxillofac Surg. 2010;14:143–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu YS, Zhang WD, Yang CH, et al. Effect of interferon alfa therapy on malignant melanoma of oral mucosa. Shanghai Kou Qiang Yi Xue. 2006;15:263–8.PubMedGoogle Scholar
  14. 14.
    Kraal JH, Hussain AA, Gregorio SB, et al. Exposure time and the effect of hexylresorcinol on bacterial aggregates. J Dent Res. 1979;58:2125–31.PubMedCrossRefGoogle Scholar
  15. 15.
    National Toxicology Program. NTP toxicology and carcinogenesis studies of 4-hexylresorcinol (CAS No. 136-77-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Toxicol Program Tech Rep Ser. 1988;330:1–166.Google Scholar
  16. 16.
    Kim SG, Jeong JH, Park YW, et al. 4-Hexylresorcinol inhibits transglutaminase-2 activity and has synergistic effects along with cisplatin in KB cells. Oncol Rep. 2011;25:1597–602.PubMedGoogle Scholar
  17. 17.
    Kim SG, Lee SW, Park YW, et al. 4-hexylresorcinol inhibits NF-κB phosphorylation and has a synergistic effect with cisplatin in KB cells. Oncol Rep. 2011;26:1527–32.PubMedGoogle Scholar
  18. 18.
    Arias E, González J, Peiró JM, et al. Browning prevention by ascorbic acid and 4-hexylresorcinol: different mechanisms of action on polyphenol oxidase in the presence and in the absence of substrates. J Food Sci. 2007;72:C464–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Thepnuan R, Benjakul S, Visessanguan W. Effect of pyrophosphate and 4-hexylresorcinol pretreatment on quality of refrigerated white shrimp (Litopenaeus vannamei) kept under modified atmosphere packaging. J Food Sci. 2008;73:S124–33.PubMedCrossRefGoogle Scholar
  20. 20.
    Shattuck-Brandt RL, Richmond A. Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. Cancer Res. 1997;57:3032–9.PubMedGoogle Scholar
  21. 21.
    Kim SG, Kim MH, Chae CH, et al. Downregulation of matrix metalloproteinases in hyperplastic dental follicles results in abnormal tooth eruption. BMB Rep. 2008;41:322–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Park YW, Kim SG, Choi JY, et al. Recapitulating orthotopic tumor model through establishment of a parotid gland tumor with lung metastasis using HeLa cell injection into nude mice. Oncol Rep. 2010;23:701–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Carlsson G, Gullberg B, Hafström L. Estimation of liver tumor volume using different formulas—an experimental study in rats. J Cancer Res Clin Oncol. 1983;105:20–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Johnson AJ, Lucas DM, Muthusamy N, et al. Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood. 2006;108:1334–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Kim SG, Hahn BD, Park DS, et al. Aerosol deposition of hydroxyapatite and 4-hexylresorcinol coatings on titanium alloys for dental implants. J Oral Maxillofac Surg. 2011;69:e354–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Lourenço SV, Sangueza MS, Sotto MN, et al. Primary oral mucosal melanoma: a series of 35 new cases from South America. Am J Dermatopathol. 2009;31:323–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of the head and neck. Head Neck. 2002;24:247–57.PubMedCrossRefGoogle Scholar
  28. 28.
    Nayak MT, Singh A, Mathur RM, et al. Second primary oral melanoma: a rare presentation. J Oral Maxillofac Pathol. 2012;16:88–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Calabrese V, Cifola M, Pareschi M, et al. Primary malignant melanomas of the oral cavity. J Laryngol Otol. 1989;103:887–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Tucci R, Aburad De Carvalhosa A, Anunciação G, et al. Late diagnosis of a primary oral malignant melanoma: a case report. Minerva Stomatol. 2010;59:55–9.PubMedGoogle Scholar
  31. 31.
    Chen QX, Ke LN, Song KK, et al. Inhibitory effects of hexylresorcinol and dodecylresorcinol on mushroom (Agaricus bisporus) tyrosinase. Protein J. 2004;23:135–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Lin YS, Chuang MT, Chen CH, et al. Nicotinic acid hydroxamate downregulated the melanin synthesis and tyrosinase activity through activating the MEK/ERK and AKT/GSK3β signaling pathways. J Agric Food Chem. 2012;60:4859–64.PubMedCrossRefGoogle Scholar
  33. 33.
    McLean N, Tighiouart M, Muller S. Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and histopathologic features of oral and sinonasal melanoma. Oral Oncol. 2008;44:1039–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Meleti M, Leemans CR, de Bree R, et al. Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of postoperative radiotherapy. Head Neck. 2008;30:1543–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Chiarion-Sileni V, Guida M, Ridolfi L, et al. Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine-based regimens. Br J Cancer. 2011;104:1816–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Lens MB, Eisen TG. Systemic chemotherapy in the treatment of malignant melanoma. Expert Opin Pharmacother. 2003;4:2205–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Jordan VC. Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer. Br J Pharmacol. 1993;110:507–17.PubMedCrossRefGoogle Scholar
  38. 38.
    Beguerie JR, Xingzhong J, Valdez RP. Tamoxifen vs. non-tamoxifen treatment for advanced melanoma: a meta-analysis. Int J Dermatol. 2010;49:1194–202.PubMedCrossRefGoogle Scholar
  39. 39.
    Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Wennerberg J, Biörklund A, Tropé C. The effect of cisplatin and fluorouracil on xenografted human squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1988;114:162–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Johnsson A, Olsson C, Nygren O, et al. Pharmacokinetics and tissue distribution of cisplatin in nude mice: platinum levels and cisplatin-DNA adducts. Cancer Chemother Pharmacol. 1995;37:23–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Tanaka T, Nakayama H, Yoshitake Y, et al. Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma. Cancer Sci. 2012;103:455–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhou CX, Gao Y, Johnson NW, et al. Immunoexpression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in the metastasis of squamous cell carcinoma of the human tongue. Aust Dent J. 2010;55:385–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Daniele A, Zito AF, Giannelli G, et al. Expression of metalloproteinases MMP-2 and MMP-9 in sentinel lymph node and serum of patients with metastatic and non-metastatic breast cancer. Anticancer Res. 2010;30:3521–7.PubMedGoogle Scholar
  45. 45.
    Hojo K, Maki H, Sawada TY, et al. Augmented growth inhibition of B16-BL6 melanoma by combined treatment with a selective matrix metalloproteinase inhibitor, MMI-166, and cytotoxic agents. Anticancer Res. 2002;22:3253–9.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Sang-Woon Lee
    • 1
  • Seong-Gon Kim
    • 1
  • Young-Wook Park
    • 1
  • HaeYong Kweon
    • 2
  • Jwa-Young Kim
    • 3
  • Horatiu Rotaru
    • 4
  1. 1.Department of Oral and Maxillofacial SurgeryGangneung-Wonju National University, College of DentistryGangneungRepublic of Korea
  2. 2.Sericultural & Apicultural Materials DivisionNational Academy of Agricultural Science, RDASuwonRepublic of Korea
  3. 3.Department of Oral and Maxillofacial SurgeryHallym UniversityAnyangRepublic of Korea
  4. 4.Department of Cranio-Maxillofacial Surgery“Iuliu Hatieganu” University of Medicine and PharmacyCluj-NapocaRomania

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