Current treatment for cutaneous T-cell lymphoma includes phototherapy, which involves either the use of narrowband ultraviolet B light or in combination with a psoralen photosensitiser. Therapy typically involves administration of the photosensitiser followed by topical exposure to . A different approach is extracorporeal photopheresis, an ex vivo strategy which is used for more advanced stages of disease. Further, histone deacetylase inhibitors are emerging as potent anticancer agents with suberoylanilide hydroxamic acid and depsipeptide, having received FDA approval for the treatment of cutaneous T-cell lymphoma. We have developed Sens, an extremely potent, DNA minor groove-binding sensitizer for potential use in phototherapy. We have previously demonstrated the extreme photopotency of Sens in human erythroleukemic K562 cells. Here we have extended those studies by investigating the photopotency of Sens in four haematological cell lines, namely, K562, T-cell leukaemic CEM-CCRF, P-glycoprotein overexpressing R100, and transformed B-lymphoblastoid cell lines (LCL) cells. In addition, we investigated the effects of suberoylanilide hydroxamic acid in combination with Sens. Using γH2AX as the endpoint, our findings indicate that Sens-induced phototoxicity in all four of the haematological cell lines. The addition of suberoylanilide hydroxamic acid augmented the photopotency of Sens highlighting the potential clinical applicability of combination therapies. 1. Introduction Cutaneous T-cell lymphoma (CTCL) describes a heterogenous series of extranodal non-Hodgkin T-cell lymphomas that primarily appear in the skin [1, 2]. CTCL is characterised by an initial influx of T-cells of the CD4 phenotype in the skin, which have the propensity to home and accumulate in the blood and lymph nodes as the disease develops [2–4]. The two most common subtypes of CTCL include mycosis fungoides (MF), generally a low-grade lymphoma characterised by skin manifestations and the erythrodermic version Sézary syndrome. Sézary syndrome is an aggressive leukemic form of the disease identifiable by diffuse skin involvement (erythroderma), lymphadenopathy, and the presence of abnormal lymphoid cells circulating in the blood [5, 6]. Although a rare condition, with annual incidence of approximately 0.2–0.8 per 100,000 [7, 8], in its advanced or transformed stages, it is a debilitating disease, differing dramatically in its clinical and histopathologic presentations and subsequent therapeutic considerations [9]. While a plethora of treatments are available for CTCL, most remain palliative,
References
[1]
R. Willemze, E. S. Jaffe, G. Burg et al., “WHO-EORTC classification for cutaneous lymphomas,” Blood, vol. 105, no. 10, pp. 3768–3785, 2005.
[2]
P. Ponte, V. Serr？o, and M. Apetato, “Efficacy of narrowband UVB vs. PUVA in patients with early-stage mycosis fungoides,” Journal of the European Academy of Dermatology and Venereology, vol. 24, no. 6, pp. 716–721, 2010.
[3]
T. Krejsgaard, K. Kopp, E. Ralfkiaer et al., “A novel xenograft model of cutaneous T-cell lymphoma,” Experimental Dermatology, vol. 19, no. 12, pp. 1096–1102, 2010.
[4]
R. L. Edelson, “Cutaneous T cell lymphoma: mycosis fungoides, Sezary syndrome, and other variants,” Journal of the American Academy of Dermatology, vol. 2, no. 2, pp. 89–106, 1980.
[5]
L. P. H. Yang, “Romidepsin: in the treatment of T-cell lymphoma,” Drugs, vol. 71, no. 11, pp. 1469–1480, 2011.
[6]
J. Y. Li, S. Horwitz, A. Moskowitz, et al., “Management of cutaneous T cell lymphoma: new and emerging targets and treatment options,” Cancer Management and Research, vol. 4, no. 1, pp. 75–89, 2012.
[7]
S. Jain and J. Zain, “Romidepsin in the treatment of cutaneous T-cell lymphoma,” Journal of Blood Medicine, vol. 2, no. 1, pp. 37–47, 2011.
[8]
H. M. Prince and M. Dickinson, “Romidepsin for cutaneous T-cell lymphoma,” Clinical Cancer Research, vol. 18, no. 13, pp. 3509–3515, 2012.
[9]
F. Glass, K. L. Keller, J. L. Messina, et al., “The diagnosis and treatment of cutaneous T-cell lymphoma are challenging due the many clnical and histopathologic presentations of the disease,” Cancer Control, vol. 5, no. 1, 1998.
[10]
E. Diamandidou, P. R. Cohen, and R. Kurzrock, “Mycosis fungoides and Sezary syndrome,” Blood, vol. 88, no. 7, pp. 2385–2409, 1996.
[11]
R. Knobler, M. L. Barr, D. R. Couriel et al., “Extracorporeal photopheresis: past, present, and future,” Journal of the American Academy of Dermatology, vol. 61, no. 4, pp. 652–665, 2009.
[12]
C. Q. Xia, K. A. Campbell, and M. J. Clare-Salzler, “Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells,” Current Opinion in Organ Transplantation, vol. 14, no. 4, pp. 338–343, 2009.
[13]
J. Scarisbrick, “Extracorporeal photopheresis: what is it and when should it be used?” Clinical and Experimental Dermatology, vol. 34, no. 7, pp. 757–760, 2009.
[14]
F. Hutchinson, “The lesions produced by ultraviolet light in DNA containing 5 bromouracil,” Quarterly Reviews of Biophysics, vol. 6, no. 2, pp. 201–246, 1973.
[15]
R. Rodriguez, E. Miller, J. F. Fowler, et al., “Continuous infusion of halogenated pyrimidines,” International Journal of Radiation Oncology, Biology, Physics, vol. 20, pp. 1380–1382, 1991.
[16]
T. C. Karagiannis, P. N. Lobachevsky, B. K. Y. Leung, J. M. White, and R. F. Martin, “Receptor-mediated DNA-targeted photoimmunotherapy,” Cancer Research, vol. 66, no. 21, pp. 10548–10552, 2006.
[17]
T. C. Karagiannis, P. N. Lobachevsky, and R. F. Martin, “DNA targeted UVA photosensitization: characterization of an extremely photopotent iodinated minor groove binding DNA ligand,” Journal of Photochemistry and Photobiology B, vol. 83, no. 3, pp. 195–204, 2006.
[18]
R. F. Martin, D. P. Kelly, M. Roberts, et al., “Comparative studies of UV-induced DNA cleavage by structural isomers of an iodinated DNA ligand,” International Journal of Radiation Biology, vol. 66, pp. 517–521, 1994.
[19]
R. F. Martin, D. P. Kelly, M. Roberts, et al., “DNA cleavage by analogues of iodoHoechst 33258,” Australian Journal of Chemistry, vol. 47, pp. 1751–1769, 1994.
[20]
V. M. Richon, “Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor,” British Journal of Cancer, vol. 95, no. 1, pp. S2–S6, 2006.
[21]
J. Tan, S. Cang, Y. Ma, R. L. Petrillo, and D. Liu, “Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents,” Journal of Hematology and Oncology, vol. 3, article 5, 2010.
[22]
B. S. Mann, J. R. Johnson, M. H. Cohen, R. Justice, and R. Pazdur, “FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma,” Oncologist, vol. 12, no. 10, pp. 1247–1252, 2007.
[23]
D. Siegel, M. Hussein, C. Belani et al., “Vorinostat in solid and hematologic malignancies,” Journal of Hematology and Oncology, vol. 2, article 31, 2009.
[24]
N. Batty, G. G. Malouf, and J. P. J. Issa, “Histone deacetylase inhibitors as anti-neoplastic agents,” Cancer Letters, vol. 280, no. 2, pp. 192–200, 2009.
[25]
C. B. Lozzio and B. B. Lozzio, “Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome,” Blood, vol. 45, no. 3, pp. 321–334, 1975.
[26]
D. M. Woodcock, S. Jefferson, M. E. Linsenmeyer et al., “Reversal of the multidrug resistance phenotype with Cremophor EL, a common vehicle for water-insoluble vitamins and drugs,” Cancer Research, vol. 50, no. 14, pp. 4199–4203, 1990.
[27]
S. A. Bateman, D. P. Kelly, R. F. Martin, and J. M. White, “DNA binding compounds. VII synthesis, characterization and DNA binding capacity of 1,2-dicarba-closo-dodecaborane bibenzimidazoles related to the DNA minor groove binder Hoechst 33258,” Australian Journal of Chemistry, vol. 52, no. 4, pp. 291–301, 1999.
[28]
L. J. Mah, A. El-Osta, and T. C. Karagiannis, “γH2AX as a molecular marker of aging and disease,” Epigenetics, vol. 5, no. 2, pp. 129–136, 2010.
[29]
L. J. Mah, R. S. Vasireddy, M. M. Tang, G. T. Georgiadis, A. El-Osta, and T. C. Karagiannis, “Quantification of gammaH2AX foci in response to ionising radiation,” Journal of Visualized Experiments, no. 38, 2010.
[30]
L. C. Sambucetti, D. D. Fischer, S. Zabludoff et al., “Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects,” Journal of Biological Chemistry, vol. 274, no. 49, pp. 34940–34947, 1999.
[31]
T. C. Karagiannis, H. Kn, and A. El-Osta, “Disparity of histone deacetylase inhibition on repair of radiation-induced DNA damage on euchromatin and constitutive heterochromatin compartments,” Oncogene, vol. 26, no. 27, pp. 3963–3971, 2007.
[32]
J. Cadet, E. Sage, and T. Douki, “Ultraviolet radiation-mediated damage to cellular DNA,” Mutation Research, vol. 571, no. 1-2, pp. 3–17, 2005.
[33]
H. Lehrmann, L. L. Pritchard, and A. Harel-Bellan, “Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation,” Advances in Cancer Research, vol. 86, pp. 41–65, 2002.
[34]
P. A. Marks, R. A. Rifkind, V. M. Richon, R. Breslow, T. Miller, and W. K. Kelly, “Histone deacetylases and cancer: causes and therapies,” Nature Reviews Cancer, vol. 1, no. 3, pp. 194–202, 2001.
[35]
Y. Shao, Z. Gao, P. A. Marks, and X. Jiang, “Apoptotic and autophagic cell death induced by histone deacetylase inhibitors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 52, pp. 18030–18035, 2004.
[36]
G. Dong, L. Wang, C. Y. Wang, T. Yang, M. V. Kumar, and Z. Dong, “Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents,” Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 3, pp. 978–984, 2008.
[37]
H. M. Amin, S. Saeed, and S. Alkan, “Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17),” British Journal of Haematology, vol. 115, no. 2, pp. 287–297, 2001.
[38]
T. Toyooka and Y. Ibuki, “Histone deacetylase inhibitor sodium butyrate enhances the cell killing effect of psoralen plus UVA by attenuating nucleotide excision repair,” Cancer Research, vol. 69, no. 8, pp. 3492–3500, 2009.
[39]
B. Briggs, K. Ververis, A. L. Rodd, L. J. L. Foong, F. M. D. Silva, and T. C. Karagiannis, “Photosensitization by iodinated DNA minor groove binding ligands: evaluation of DNA double-strand break induction and repair,” Journal of Photochemistry and Photobiology B, vol. 103, no. 2, pp. 145–152, 2011.
[40]
K. L. Cann and G. G. Hicks, “Regulation of the cellular DNA double-strand break response,” Biochemistry and Cell Biology, vol. 85, no. 6, pp. 663–674, 2007.
[41]
A. Kinner, W. Wu, C. Staudt, and G. Iliakis, “Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin,” Nucleic Acids Research, vol. 36, no. 17, pp. 5678–5694, 2008.
[42]
E. C. Friedberg, “DNA damage and repair,” Nature, vol. 421, no. 6921, pp. 436–440, 2003.
[43]
L. J. Mah, A. El-Osta, and T. C. Karagiannis, “γh2AX: a sensitive molecular marker of DNA damage and repair,” Leukemia, vol. 24, no. 4, pp. 679–686, 2010.
[44]
J. S. Dickey, C. E. Redon, A. J. Nakamura, B. J. Baird, O. A. Sedelnikova, and W. M. Bonner, “H2AX: functional roles and potential applications,” Chromosoma, vol. 118, no. 6, pp. 683–692, 2009.
[45]
N. Kartner and V. Ling, “Multidrug resistance in cancer,” Scientific American, vol. 260, no. 3, pp. 44–51, 1989.
[46]
E. K. Baker and A. El-Osta, “The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer,” Experimental Cell Research, vol. 290, no. 2, pp. 177–194, 2003.
[47]
T. Litman, T. E. Druley, W. D. Stein, and S. E. Bates, “From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance,” Cellular and Molecular Life Sciences, vol. 58, no. 7, pp. 931–959, 2001.
[48]
A. F. List, K. J. Kopecky, C. L. Willman et al., “Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study,” Blood, vol. 98, no. 12, pp. 3212–3220, 2001.
[49]
G. Miller and M. Lipman, “Comparison of the yield of infectious virus from clones of human and simian lymphoblastoid lines transformed by Epstein Barr virus,” The Journal of Experimental Medicine, vol. 138, no. 6, pp. 1398–1412, 1973.
[50]
J. Werner, G. Henle, C. A. Pinto, R. F. Haff, and W. Henle, “Establishment of continuous lymphoblast cultures from leukocytes of gibbons (Hylobates lar),” International Journal of Cancer, vol. 10, no. 3, pp. 557–567, 1972.
[51]
M. J. Peart, K. M. Tainton, A. A. Ruefli et al., “Novel mechanisms of apoptosis induced by histone deacetylase inhibitors,” Cancer Research, vol. 63, no. 15, pp. 4460–4471, 2003.
