Abstract #255A: Hypoxia impedes ovarian cancer treatment through modulation of ROS and STAT3 activation: An implication of HBOT therapy
Authors: Karuppaiyah Selvendiran, Anna Bratasz, M. Lakshmi Kuppusamy, Mahmood Khan, Brian Rivera, Periannan Kuppusamy
Journal: Cancer Research (2009)

Hypoxic microenvironments are frequently found in solid tumors. Hypoxia plays critical roles in tumor progression including tumor angiogenesis, mutation rate, metastasis and resistance to radiation and chemotherapy. Recently, using in vivo electron paramagnetic resonance (EPR) oximetry, we observed that the oxygen concentration in human ovarian tumor xenografts in mice was severely hypoxic. Hence we performed a series of in vitro pilot experiments to compare protein expression in cells grown under hypoxic conditions (1% oxygen), versus cells grown under normoxic (20% oxygen) conditions. This series of experiments revealed that hypoxic conditions elicit an overexpression of pSTAT3-Tyr705 when compared to cells grown under normoxic conditions. STAT3 is overexpressed in a variety of human cancers, including ovarian cancer, and especially in solid tumor forms of ovarian cancer. Inhibition of STAT3 expression results in apoptosis of tumor cells. Therefore, STAT3 is considered to be an attractive target for anticancer therapy. However, the molecular mechanism by which the STAT3 gene is upregulated in tumor cells is poorly understood. We found that pSTAT3 was significantly upregulated by hypoxia, which was also accompanied by increased reactive oxygen species (ROS) generation in human ovarian cancer cell lines. In addition, the efficacy of the common anticancer drugs cisplatin and taxol was reduced in hypoxia-treated ovarian cancer cells when compared to normoxia-cultured cells, possibly due STAT3 overexpression-induced resistance to anticancer drugs. Furthermore, inhibition of STAT3 expression using the JAK inhibitor AG490 or the novel curcumin analog HO-3867, followed by treatment with cisplatin or Taxol resulted in a more than two-fold increase in induced apoptosis when compared to hypoxia-cultured cells that were not treated with AG490 and HO-3867. We have also found that ovarian tumor-bearing mice subjected to daily hyperbaric oxygen therapy (HBOT; 100% O2 at 2 atmospheres, absolute) for a period of 90 minutes for a total of 14 days had significantly reduced tumor volume when compared to untreated controls. Post-mortem Western blot analysis of tumor tissues showed an inhibition of STAT3 expression in ovarian tumors recovered from HBOT-treated animals. Taken together, these results indicate that STAT3 is upregulated by hypoxia in vitro, and that hypoxia-induced chemoresistance is at least partially due to STAT3 upregulation. This chemoresistance can be reversed through inhibition of STAT3 expression using AG490 or the novel curcumin analog HO-3867. We also observed an increase in ROS generation in ovarian cancer cells cultured under hypoxic conditions. In a pilot series of in vivo experiments using a murine model of ovarian cancer, HBOT has been shown to inhibit hypoxic ovarian tumor growth through a reduction in STAT3 expression.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 255A.