[Cancer Biology & Therapy 3:7, 612-613, July 2004]; ©2004 Landes Bioscience
Histone Deacetylase Inhibitors are Potent Radiation Protectants Journal Club
*Correspondence to: William Douglas Figg; Cancer Therapeutics Branch; Center for Cancer Research; National Cancer Institute; Bldg.10 / Room 5A01 MSC 1910; 9000 Rockville Pike; Bethesda, Maryland 20892 USA; Tel.: +1.301.402.3622; Fax: +1.301.402.8606; Email:
[email protected] Received 04/16/04; Accepted 04/19/04
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DISCUSSION
Acetylation and deacetylation play important roles in the regulation of gene transcription by the modulation of chromatin structure. Histone deacetylase inhibitors are a new class of cytostatic drugs that have been shown to induce cell cycle arrest in G1 phase, inhibition of proliferation, differentiation and/or apoptosis in tumor cell lines. Histone hyperacetylation may lead to the upregulation of cell cycle inhibitors such as p21Cip1, p27Kip1 and p16INK4, the downregulation of oncogenes such as Myc and Bcl-2, and the repression of inflammatory cytokines like IL-1, IL-8, TNF-α, TGF-β.1-6 Radiotherapy is critically important in the treatment of some neoplasia, such as head and neck, skin and anogenital cancer however, acute and long-term side effects (such as fibrosis and late tumorigenesis) represent a clinical problem that may limit radiotherapy’s benefits. Topical treatments based on steroidal or nonsteroidal anti-inflammatories have often shown disappointing results in terms of control of the so-called cutaneous radiation syndrome while other compounds (amifostine, prostaglandins, vitamins, anti-fibrogenic agents) have been shown to potentially ameliorate only limited aspects of radiation-related toxicities.7,8 Chung et al.9 have shown that topical treatment with histone deacetylase inhibitors such as phenylbutyrate (PB), trichostatin A and valproic acid are able to ameliorate or suppress cutaneous radiation syndrome. PB in particular, on which the study primarily focused, also showed a decrease in later skin fibrosis and tumorigenesis in animal models. The authors evaluated the development of acute skin reactions after irradiation of four groups of five rats receiving vaseline (negative control), madecassol (positive control), cream vehicle or different HDAC inhibitors. The average skin scores from day 1 to day 90 revealed significant lower values for the PB-treated group compared to the vehicle (p < 0.001). Histology of reaction after irradiation in the PB-group demonstrated less radiation-related proliferative dermal fibrosis compared to the vehicle at day 180, the controls of normal skin at day 0 and acute reaction at day 7. Considering that TNF-α and TGF-β may be involved in the amplified injury response to radiation,10,11 the authors subsequently analyzed the expression levels of these two cytokines after irradiation. In the PB-group the analysis of mRNA levels for TGF-β1, TGF-β2 and TNF-α revealed suppression values after day 14, levels similar to the nonirradiated controls at day 28–35 and persistence of suppression at 12 months, even after the discontinuation of treatment with PB at day 90. Immunofluorescence analysis confirmed low levels of TGF-β in the PB-group versus the vehicle group in epidermis and dermis at day 180. Immunohistochemistry for TNF-α showed low levels of its expression in the normal skin and PB-group in contrast with high values in the vaseline and vehicle groups where it correlated with skin necrosis and heavy inflammatory infiltrates. The development of tumors such as sarcoma, squamous and basal cell carcinomas represent one of the possible sequelae of radiotherapy. Topical treatment with PB showed prevention of late radiation-induced skin tumor formation in mice and a direct antitumor effect on cutaneous growth of cancer cells. A cumulative tumor incidence of 15% was observed in the irradiated animals without PB treatment versus 0% in the PB-group at 90
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Previously published online as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cbt/abstract.php?id=931
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of Medical Oncology; Regina Elena Cancer Institute; Rome, Italy
Therapeutics Branch; Center for Cancer Research; National Cancer Institute; Bethesda, Maryland USA 2Cancer
Radiation-induced acute and late injuries often represent a limit to the optimal delivery of radiotherapy in cancer patients. Chung et al. reported that histone deacetylase (HDAC) inhibitors, a novel class compound of gene modulators, might have a role in controlling different adverse effects from radiotherapy in preclinical models. They also showed how protection of normal tissues and inhibition of tumor growth might be possible at the same time.
KEY WORDS
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histone deacetylase inhibitors, phenylbutyrate, cutaneous radiation syndrome, radiotherapy
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ABSTRACT
Luca Paoluzzi1,2 William D. Figg2,*
ABBREVIATIONS
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HDAC histone deacetylase PB phenylbutyrate
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Cancer Biology & Therapy
2004; Vol. 3 Issue 7
HISTONE DEACETYLASE INHIBITORS ARE POTENT RADIATION PROTECTANTS
weeks, and the tumor sizes of carcinoma cells in the placebo groups were as great as approximately 6 times larger than those in the PB group. Doses and frequency of radiation treatments are important variables in effectively controlling tumor growth. Severe acute side effects and later complications often represent the high price that patients have to pay in order to obtain a satisfactory cure or palliation. In preclinical models HDAC inhibitors appear to have multiple targets with the potential ability to control the acute and subsequent side effects of radiotherapy, in particular they seem to be able to combine antiinflammatory and anti-fibrotic effects with a possible reduced incidence of late tumorigenesis. Phase I clinical trials are showing an interesting profile of tolerability for these agents, with the possibility to achieve the concentrations in vivo that have been shown to have biological activity in vitro. These studies hypothesize a role for PB as a cytostatic agent in combination with cytotoxic or other anti-cancer agents.12-15 Of course, many questions still remain unanswered regarding the best way, if any, to introduce these emerging agents in cancer prevention and/or treatment as well as their hypothetical utilization in combination with radio- and radiochemotherapy strategies. This work suggests a new and advisable area of research for HDAC inhibitors—one that advocates the use of some of these novel compounds as a helpful instrument in the management of anti-cancer treatment related toxicities. References 1. Figg WD, Walls RG, Cooper MR, Thibault A, Sartor O, McCall NA, et al. In vitro antitumor effect of hydroxyurea on hormone-refractory prostate cancer cells and its potentiation by phenylbutyrate. Anticancer Drugs 1994; 5:336-42. 2. Boudoulas S, Lush RM, McCall NA, Samid D, Reed E, Figg WD. Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents. Ther Drug Monit. 1996; 18:714-20. 3. Melchior SW, Brown LG, Figg WD, Quinn JE, Santucci RA, Brunner J, et al. Effects of phenylbutyrate on proliferation and apoptosis in human prostate cancer cells in vitro and in vivo. Int J Oncol 1999; 14:501-8. 4. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitor: Induction of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000; 92:1210-6. 5. Richon VM, O’Brien JP. Histone deacetylase inhibitors: A new class of potential therapeutic agents for cancer treatment. Clin Cancer Res 2002; 9:662-7. 6. Vigushin DM, Coombes RC. Targeted histone deacetylase inhibition for cancer therapy Curr Cancer Drug Targets 2004; 4:205-18. 7. Grdina DJ, Murley JS, Kataoka Y. Radioprotectants: Current status and new directions. Oncology 2002; 63:2-10. 8. Lee TK, Stupans L. Radioprotection: The nonsteroidal anti-inflammatory drugs (NSAIDs) and prostaglandins. J Pharm Pharmacol 2002; 54:1435-45. 9. Chung YL, Wang AJ, Yao LF. Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy. Mol Cancer Ther 2004; 3:317-25. 10. Zhou D, Yu T, Chen G, Brown SA, Yu Z, Mattson MP, et al. Effects of NF-kappaB1 (p50) targeted gene disruption on ionizing radiation-induced NF-kappa B activation and TNFα, IL-1α, IL-1β and IL-6 mRNA expression in vivo. Int J Radiat Biol Jul 2001; 77:763-72. 11. Sivan V, Vozenin-Brotons MC, Tricaud Y, Lefaix JL, Cosset JM, Dubray B, et al. Altered proliferation and differentiation of human epidermis in cases of skin fibrosis after radiotherapy. Int J Radiat Oncol Biol Phys Jun 1 2002; 53:385-93. 12. Gilbert J, Baker SD, Bowling MK Grochow L, Figg WD, Zabelina Y, et al. A phase I dose escalation and biovailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 2001; 7:2292-300. 13. Carducci MA, Gilbert J, Bowling MK, Noe D, Eisenberger MA, Sinibaldi V, et al. A phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin Cancer Res 2001; 7:3047-55. 14. Gore SD, Weng LJ, Zhai S, Figg WD, Donehower RC, Dover GJ, et al. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res Aug 2001; 7:2330-9. 15. Gore SD, Weng LJ, Figg WD, Zhai S, Donehower RC, Dover G, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res Apr 2002; 8:963-70.
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