Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

被引:53
作者
Cantor, Joshua P.
Iliopoulos, Dimitrios
Rao, Atul S.
Druck, Teresa
Semba, Shuho
Han, Shuang-Yin
McCorkell, Kelly A.
Lakshman, Thiru V.
Collins, Joshua E.
Wachsberger, Phyllis
Friedberg, Joseph S.
Huebner, Kay
机构
[1] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
[2] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA
[3] Stanford Univ, Med Ctr, Stanford, CA USA
[4] Thomas Jefferson Univ, Dept Microbiol & Immunol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[5] Thomas Jefferson Univ, Dept Radiat Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
关键词
DNA methylation; tumor suppressor genes; 5-aza-2-deoxycytidine;
D O I
10.1002/ijc.22073
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and historic deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenctically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox' p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16 INK,, Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. (c) 2006 Wiley-Liss, Inc.
引用
收藏
页码:24 / 31
页数:8
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