Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 9, September, p. 1039–1049

doi: 10.17219/acem/124439

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Anticancer activity of topical ointments with histone deacetylase inhibitor, trichostatin A

Agnieszka Chodkowska1,A,B,C,D,E,F, Alicja Bieńkowska1,C,D,E, Żaneta Słyk1,B, Joanna Giebułtowicz2,B,D, Maciej Małecki1,A,C,E,F

1 Department of Applied Pharmacy, Faculty of Pharmacy, Medical University of Warsaw, Poland

2 Department of Bioanalysis and Drugs Analysis, Faculty of Pharmacy, Medical University of Warsaw, Poland

Abstract

Background. Trichostatin A (TSA), being a strong specific histone deacetylase (HDAC) inhibitor, may lead to the inhibition of growth, differentiation and/or apoptosis of cells in a number of tumors. Semisolid drug formulations for topical release of anticancer agents may be an alternative strategy or a supplement of the systemic therapy.
Objectives. To prepare semisolid formulations with TSA to be used directly on the skin and to assess the anticancer effect in vivo on a mouse model with L1 neoplastic tumors.
Material and Methods. Twenty-four formulations were prepared in the form of semisolid systems containing TSA as the active ingredient. Then, an in vitro study was performed concerning the release of the active substance from the prepared formulations. Four formulations were selected for in vivo studies: oil-in-water cream, hydrogel, w/o emulsion ointment on the absorptive hydrophobic medium, and o/w emulsion gel. The tumor size and mouse body weight were measured during the experiment. The tumors and healthy skin of the mice were assessed regarding the skin barrier function with the Corneometer and Tewameter probes.
Results. The semisolid formulation with TSA applied on the skin reduced the growth of neoplastic tumors as compared with the control group. This is especially pronounced in the case of w/o emulsion ointment and o/w emulsion gel. The Corneometer shows that neoplastic tumor growth and formulations on the skin have no effect on the skin condition in comparison with the mouse skin without tumor. The measurement performed with the Tewameter has revealed impaired skin barrier function of neoplastic tumors.
Conclusion. Semisolid formulations with TSA fit well in the mainstream of research into topical medicines applied directly on neoplastic tumors, which may support and supplement current oncological treatment.

Key words

trichostatin A, anticancer topical formulations, ointments, skin cream, cancer applied pharmacy

References (55)

  1. International Agency for Research on Cancer. https://gco.iarc.fr/tomorrow/home. Accessed August 24, 2020.
  2. Krajowy Rejestr Nowotworów. http://onkologia.org.pl/nowotwory-zlosliwe-ogolem-2/. Accessed August 24. 2020.
  3. Chessum N, Jones K, Pasqua E, Tucker M. Recent advances in cancer therapeutics. Prog Med Chem. 2015;54:1–63. doi:10.1016/bs.pmch.2014.11.002
  4. Collins I, Workman P. New approaches to molecular cancer therapeutics. Nat Chem Biol. 2006;2(12):689–700.
  5. Grabarska A, Dmoszyńska-Graniczka M, Nowosadzka E, Stepulak A. Histone deacetylase inhibitors: Molecular mechanisms of actions and clinical applications. Postepy Hig Med Dosw (Online). 2013;67:722–735.
  6. Smith LT, Otterson GA, Plass C. Unraveling the epigenetic code of cancer for therapy. Trends Genet. 2007;23(9):449–456.
  7. Kudo K, Ozaki T, Shin-ya K, Nishiyama M, Kuzuyama T. Biosynthetic origin of the hydroxamic acid moiety of trichostatin A: Identification of unprecedented enzymatic machinery involved in hydroxylamine transfer. J Am Chem Soc. 2017;139(20):6799–6802. doi:10.1021/jacs.7b02071
  8. Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y, Koizumi K. A new antifungal antibiotic, trichostatin. J Antibiot (Tokyo). 1976;29(1):1–6. doi.org/10.7164/antibiotics.29.1
  9. Yoshida M, Horinouchi S, Beppu T. Trichostatin A and trapoxin: Novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays. 1995;17(5):423–430. doi:10.1002/bies.950170510
  10. Kim SH, Kang HJ, Na H, Li MO. Trichostatin A enhances acetylation as well as protein stability of ERalpha through induction of p300 protein. Breast Cancer Res. 2010;12(2):R22. doi:10.1186/bcr2562
  11. Sharma P, Kumar S, Kundu GC. Transcriptional regulation of human osteopontin promoter by histone deacetylase inhibitor, trichostatin A in cervical cancer cells. Mol Cancer. 2010;9:178. doi:10.1186/1476-4598-9-178
  12. Cheng DD, Yang QC, Zhang ZC, Yang CX, Liu YW. Antitumor activity of histone deacetylase inhibitor trichostatin A in osteosarcoma cells. Asian Pac J Cancer Prev. 2012;13(4):1395–1399. doi:10.7314/apjcp.2012.13.4.1395
  13. Park H, Lee YJ, Kim TH, et al. Effects of trichostatin A, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells. Int J Mol Med. 2008;22(5):605–611.
  14. Geng Y, Liu J, Xie Y, et al. Trichostatin A promotes GLI1 degradation and P21 expression in multiple myeloma cells. Cancer Manag Res. 2018;10:2905–2914. doi:10.2147/CMAR.S167330
  15. Hakami NY, Dusting GJ, Peshavariya HM. Trichostatin A, a histone deacetylase inhibitor suppresses NADPH oxidase 4-derived redox signaling and angiogenesis. J Cell Mol Med. 2016;20(10):1932–1944. doi:10.1111/jcmm.12885
  16. Hajji N, Wallenborg K, Vlachos P, Nyman U, Hermanson O, Joseph B. Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIF-dependent apoptotic cell death in non-small cell lung carcinoma cells. Oncogene. 2008;27(22):3134–3144.
  17. Wu J, Hu CP, Gu QH, Li YP, Song M. Trichostatin A sensitizes cisplatin-resistant A549 cells to apoptosis by up-regulating death-associated protein kinase. Acta Pharmacol Sin. 2010;31(1):93–101. doi:10.1038/aps.2009.183
  18. Zhang XF, Yan Q, Shen W, Gurunathan S. Trichostatin A enhances the apoptotic potential of palladium nanoparticles in human cervical cancer cells. Int J Mol Sci. 2016;17(8):1354. doi:10.3390/ijms17081354
  19. Suraweera A, O’Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Front Oncol. 2018;8:92. doi:10.3389/fonc.2018.0009
  20. Ghiciuc CM, Strat AL, Ochiuz L, et al. Inhibition of bcl-2 and cox-2 protein expression after local application of a new carmustine-loaded clinoptilolite-based delivery system in a chemically induced skin cancer model in mice. Molecules. 2017;22(11):2014. doi:10.3390/molecules22112014
  21. Shakeel F, Haq N, Al-Dhfyan A, Alanazi FK, Alsarra IA. Chemoprevention of skin cancer using low HLB surfactant nanoemulsion of 5-fluorouracil: A preliminary study. Drug Deliv. 2015;22(4):573–580. doi:10.3109/10717544.2013.868557
  22. Pharmacopoea Polonica Editio XI. Vol. I. Warszawa, Poland: Polskie Towarzystwo Farmaceutyczne; 2017:122.
  23. Sznitowska M. Farmacja stosowana. Technologia postaci leku. Warszawa, Poland: PZWL; 2017;369–442, 883–930.
  24. Seppic SA. https://www.seppic.com/en/technologies/polymerization. Accessed August 24, 2020.
  25. Bonacucina G, Cespi M, Palmieri GF. Characterization and stability of emulsion gels based on acrylamide/sodium acryloyldimethyl taurate copolymer. AAPS PharmSciTech. 2009;10(2):368–375. doi:10.1208/s12249-009-9218-1
  26. Janik P, Szaniawska B. Search for an influence of natural immunity on the lung colony assay of a syngeneic transplanted murine tumour. Br J Cancer. 1978;37(6):1083–1085. doi:10.1038/bjc.1978.157
  27. Vigushin DM, Ali S, Pace PE, et al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res. 2001;7(4):971–976.
  28. Ali NS, Akudugu JM, Howell RH. A preliminary study on treatment of human breast cancer xenografts with a cocktail of paclitaxel, doxorubicin, and 131I-anti-epithelial cell adhesion molecule (9C4). World J Nucl Med. 2019;18(1):18–24. doi:10.4103/wjnm.WJNM_9_18
  29. Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989;24(3):148–154. doi:10.1007/bf00300234
  30. https://www.courage-khazaka.de/en/scientific-products/all-products/16-wissenschaftliche-produkte/alle-produkte/183-corneometer-e. Accessed August 24, 2020.
  31. https://www.courage-khazaka.de/en/scientific-products/all-products/16-wissenschaftliche-produkte/alle-produkte/257-tewameter-hex-e. Accessed August 24, 2020.
  32. Lodén M, Hagforsen E, Lindberg M. The presence of body hair influences the measurement of skin hydration with the Corneometer. Acta Derm Venereol. 1995;75(6):449–450. doi:10.2340/0001555575449450
  33. Wakeman MP. An open-label forearm-controlled pilot study to assess the effect of a proprietary emollient formulation on objective parameters of skin function of eczema-prone individuals over 14 days. Clin Cosmet Investig Dermatol. 2017;10:275–283. doi:10.2147/CCID.S135841
  34. De Paepe K, Houben E, Adam R, Wiesemann F, Rogiers V. Validation of the VapoMeter, a closed unventilated chamber system to assess transepidermal water loss vs the open chamber Tewameter. Skin Res Technol. 2005;11(1):61–69. doi:10.1111/j.1600-0846.2005.00101.x
  35. Lunter DJ, Daniels R. New film forming emulsions containing Eudragit® NE and/or RS 30D for sustained dermal delivery of nonivamide. Eur J Pharm Biopharm. 2012;82(2):291–298.
  36. Dyja R, Jankowski A. The effect of additives on release and in vitro skin retention of flavonoids from emulsion and gel semisolid formulations. Int J Cosmet Sci. 2017;39(4):442–449. doi:10.1111/ics.12395
  37. Sarkar R, Banerjee S, Amin SA, Adhikari N, Jha T. Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review. Eur J Med Chem. 2020;192:112171. doi:10.1016/j.ejmech.2020.112171
  38. Pucci C, Martinelli C, Ciofani G. Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedical­science. 2019;13:961. doi:10.3332/ecancer.2019.961
  39. Stoff JA. Selected office-based anticancer treatment strategies. J Oncol. 2019;2019:7462513. doi:10.1155/2019/7462513
  40. Zhang H, Shang YP, Chen HY, Li J. Histone deacetylases function as novel potential therapeutic targets for cancer. Hepatol Res. 2017;47(2):149–159. doi:10.1111/hepr.12757
  41. Schizas D, Mastoraki A, Naar L, et al. Concept of histone deacetylases in cancer: Reflections on esophageal carcinogenesis and treatment. World J Gastroenterol. 2018;24(41):4635–4642. doi:10.3748/wjg.v24.i41.4635
  42. Singh AK, Bishayee A, Pandey AK. Targeting histone deacetylases with natural and synthetic agents: An emerging anticancer strategy. Nutrients. 2018;10(6):731. pii: E731. doi:10.3390/nu10060731
  43. Kalin JH, Eroglu A, Liu H, et al. Investigation into the use of histone deacetylase inhibitor MS-275 as a topical agent for the prevention and treatment of cutaneous squamous cell carcinoma in an SKH-1 hairless mouse model. PLoS One. 2019;14(3):e0213095. doi:10.1371/journal.pone.0213095
  44. Sanaei M, Kavoosi F. Histone deacetylases and histone deacetylase inhibitors: Molecular mechanisms of action in various cancers. Adv Biomed Res. 2019;8:63. doi:10.4103/abr.abr_142_19
  45. Ma J, Guo X, Zhang S, et al. Trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and promotes apoptosis of esophageal squamous cell lines. Mol Med Rep. 2015;11(6):4525–4531. doi:10.3892/mmr.2015.3268
  46. Calienni MN, Febres-Molina C, Llovera RE, et al. Nanoformulation for potential topical delivery of Vismodegib in skin cancer treatment. Int J Pharm. 2019;565:108–122. doi:10.1016/j.ijpharm.2019.05.002
  47. Kubicki SL, Park KE, Aung PP, Duvic M. Complete resolution of primary cutaneous anaplastic large cell lymphoma with topical imiquimod. J Drugs Dermatol. 2019;18(5):460–462.
  48. Tio DCKS, van Montfrans C, Ruijter CGH, Hoekzema R, Bekkenk MW. Effectiveness of 5% topical imiquimod for lentigo maligna treatment. Acta Derm Venereol. 2019;99(10):884–888. doi:10.2340/00015555-3241
  49. Bahramizadeh M, Bahramizadeh M, Kiafar B, et al. Development, characterization and evaluation of topical methotrexate-entrapped deformable liposome on imiquimod-induced psoriasis in a mouse model. Int J Pharm. 2019;569:118623. doi:10.1016/j.ijpharm.2019.118623
  50. Shahid M, Subhan F, Ahmad N, Sewell RDE. Efficacy of a topical gabapentin gel in a cisplatin paradigm of chemotherapy-induced peripheral neuropathy. BMC Pharmacol Toxicol. 2019;20(1):51. doi:10.1186/s40360-019-0329-3
  51. Kanaya R, Kase S, Ishijima K, Ishida S. Usefulness of topical interferon alpha-2b eye drop as an adjunctive therapy following surgical resection in ocular surface squamous neoplasia. In Vivo. 2019;33(6):2211–2215. doi:10.21873/invivo.11724
  52. Bolek B, Wylęgała A, Teper S, Kokot J, Wylęgała E. Treatment of conjunctival papilloma with topical interferon alpha-2b: Case report. Medicine (Baltimore). 2020;99(7):e19181. doi:10.1097/MD.0000000000019181
  53. Dewan MZ, Vanpouille-Box C, Kawashima N, et al. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin Cancer Res. 2012;18(24):6668–6678. doi:10.1158/1078-0432.CCR-12-0984
  54. Sznitowska M, Kaliszan R. Biofarmacja. Wrocław, Poland: Elsevier Urban & Partner; 2014:221–234.
  55. Dai W, Wang C, Yu C, et al. Preparation of a mixed-matrix hydrogel of vorinostat for topical administration on the rats as experimental model. Eur J Pharm Sci. 2015;78:255–263. doi:10.1016/j.ejps.2015.07.019
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