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NCX-4016, a nitro-derivative of aspirin, inhibits EGFR and STAT3 signaling and modulates Bcl-2 proteins in cisplatin-resistant human ovarian cancer cells and xenografts.

Abstract
We have previously reported the inhibitory effect of NCX-4016, a nitro derivative of aspirin, on the proliferation of cisplatin-resistant human ovarian cancer cells, in vitro (Bratasz et al., Proc Natl Acad Sci USA 2006; 103:3914-9). In this report we present the results of our study on the mechanistic aspects of drug action including the molecular and signaling pathways involved in an in vitro cell line, as well as in a murine tumor xenograft. We report, for the first time, that NCX-4016 significantly inhibited the growth of cisplatin-resistant human ovarian cancer xenografts in mice. We observed that the inhibitory effect of NCX-4016 on cell proliferation was associated with G(1) phase cell cycle arrest with increased activity of p53, p21 and p27 proteins. NCX-4016 modulated the Bcl-2 family of proteins, and induced apoptosis by activating Bax and cytochrome c release in a time-dependent manner. In addition, NCX-4016 selectively down-regulated the phosphorylated forms of EGFR (Tyr845, Tyr992), pAkt (Ser473, Thr305), and STAT3 (Tyr705, Ser727), in vitro and in vivo. Taken together, the results clearly suggested that NCX-4016 causes significant induction of cell cycle arrest and apoptosis in cisplatin-resistant human ovarian cancer cells via down-regulation of EGFR/PI3K/STAT3 signaling and modulation of Bcl-2 family proteins. Thus, NCX-4016 appears to be a potential therapeutic agent for treating recurrent human ovarian carcinoma.
AuthorsKaruppaiyah Selvendiran, Anna Bratasz, Liyue Tong, Louis J Ignarro, Periannan Kuppusamy
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 7 Issue 1 Pg. 81-8 (Jan 01 2008) ISSN: 1551-4005 [Electronic] United States
PMID18196976 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Proto-Oncogene Proteins c-bcl-2
  • STAT3 Transcription Factor
  • ErbB Receptors
  • nitroaspirin
  • Cisplatin
  • Aspirin
Topics
  • Animals
  • Aspirin (analogs & derivatives, chemistry, pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Cisplatin (pharmacology, therapeutic use)
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm (drug effects, physiology)
  • ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics, metabolism)
  • STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
  • Signal Transduction (drug effects, physiology)
  • Transplantation, Heterologous (pathology)

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