Abstract #3620: The parthenolide analog DMAPT induces X-ray sensitization of radiation resistant lung cancer cells through inhibition of NF-\#954;B dependent split dose recovery and DNA double strand break repair

We have shown that parthenolide, a sesquiterpene lactone isolated from the Feverfew plant, sensitize human prostate and CGL1 cells to X-ray induced cell killing. We have now investigated whether DMAPT, a more bioavailable derivative of parthenolide, is able to sensitize radiation resistant A549 and H1299 human lung cancer cells to X-ray induced cell killing. We found that DMAPT inhibits constitutive and radiation-induced NF-\#954;B binding activity in both lung cancer cells. In addition, parthenolide and DMAPT were potent radiation sensitizers, with a dose modification factor of 1.5 to 1.7, for these human lung cancers regardless of p53 status. Cell cycle analysis suggested that some of the radiosensitization induced by DMAPT might be due to altered cell cycle distribution. However, we have now clearly demonstrated that the X-ray sensitization involves inhibition of split-dose recovery and DNA double strand break repair. To test whether it was DMAPT\#8217;s inhibition of NF-\#954;B activity that is responsible for the above X-ray sensitization, we performed siRNA knockdown of p65, an active NF-\#954;B family member, in both lung cancer cells. We found that knock down of p65 significantly increased radiation sensitivity and completely inhibited split-dose recovery in a very similar manner as DMAPT treatment alone. Taken together the data indicate that DMAPT is a relatively nontoxic, potent radiation sensitizer of resistant lung cancer cells and it is inhibition of NF-\#954;B that leads to the observed X-ray sensitization. DMAPT has excellent potential for clinical translation to enhance X-ray treatment of radiation-resistant lung cancers.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3620.