Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Original Article - click here for text.

The Pharmacogenomics Journal advance online publication 17 November 2009; doi: 10.1038/tpj.2009.49

A K Maiti¹

¹A&I, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

Correspondence: Dr AK Maiti, A&I, Oklahoma Medical Research Foundation, 825 NE13th, Oklahoma City, OK 73104, USA. E-mails: amit-maiti@omrf.org, Akmit123@yahoo.com

Received 23 March 2009; Revised 21 August 2009; Accepted 24 September 2009; Published online 17 November 2009.

Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug- and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H₂O₂, COS (chronic oxidative stress) or NOO^-. The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl^cos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl^cos cells than in Cbl-treated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl^cos-treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl^cos cells.