Dacogen MOA preclinical
[imho, epigenetics will positively surprise within the next decade]
31 March 2005, Volume 24, Number 14, Pages 2386-2397
Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells
Federico A Steiner1, Julie A Hong1, Maria R Fischette1, David G Beer2, Zong-Sheng Guo1, G Aaron Chen1, Todd S Weiser1, Edmund S Kassis1, Dao M Nguyen1, Sunmin Lee3, Jane B Trepel3 and David S Schrump1
Space
1Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2Thoracic Surgery Section, University of Michigan Medical Center, Ann Arbor, MI, USA
3Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Correspondence to: DS Schrump, Thoracic Oncology Section, Surgery Branch, National Cancer Institute, Building 10, Room 4-3942, 10 Center Drive MSC1201, Bethesda, MD 20892-1201, USA. E-mail: david_schrump@nih.gov
Abstract
cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2'-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.
Oncogene (2005) 24, 2386-2397. doi:10.1038/sj.onc.1208376
Published online 7 February 2005
TFPI-2; 5-aza 2'-deoxycytidine; depsipeptide FK228; lung cancer; esophageal cancer
Received 13 June 2003; revised 1 November 2004; accepted 1 November 2004; published online 7 February 2005 |
