Abstract A61: Ischemic preconditioning agents sensitize cancer cells to oxidative stress
Authors: Kesaraju Shailaja , Sur Arunodoy , Ayyanathan Kasirajan , Weissbach Herbert 
Published: January 2014

A major challenge in cancer therapy is to develop drugs that kill tumor cells without being toxic to normal cells. More than 15 years ago, sulindac and related compounds were shown to have anti-tumor activity that did not appear to be related to sulindac's anti-inflammatory activity. This proposal is based on the unique properties of sulindac that we have observed that are unrelated to its NSAID activity. This drug can protect certain normal cells, such as lung, retinal pigment epithelial cells (RPE) and cardiac cells, against oxidative stress, but markedly enhance the killing of all cancer cells tested in the presence of oxidative stress. The protection of cardiac cells against ischemia/reperfusion oxidative damage by sulindac has been shown to be due to an ischemic preconditioning mechanism. We believe that sulindac, in the presence of any compound that affects mitochondrial respiration resulting in ROS formation, causes cancer cell death due to apoptosis. Our hypothesis is that sulindac, and other ischemic preconditioning agent (IPC) in combination with agents that cause oxidative stress, initiate a protective preconditioning response to oxidative stress in normal cells, but trigger an apoptotic response to oxidative stress in cancer cells. Our preliminary results have shown a most important new and unique observation, that other known ischemic preconditioning agents, such as sildenafil can substitute for sulindac and enhance the killing of cancer cells exposed to oxidative stress.

We tested for the most active drug combination of IPC agents on the viability of three different cancer cell lines, retinoblastoma (Rb), lung (A549) and glioblastoma (U87) using either sulindac or sildenafil in combination with anti-cancer agents that cause mitochondrial dysfunction such as doxorubicin (DOX), DCA and arsenic trioxide (As2O3). Our results show that enhanced cancer killing was seen with all the three cancer cell lines using either sulindac/sildenafil with both DOX and DCA whereas enhanced killing with As2O3 was observed only in A549 cells highlighting the metabolic differences in the cell lines. In order to confirm that sulindac and sildenafil are acting as preconditioning agents, we used normal RPE cells and exposed them to UV radiation to produce oxidative damage in the presence or absence of sulindac/sildenafil. Both sulindac and sildenafil significantly protected the RPE cells against UV induced damage. We obtained preliminary evidence on the role of PKC (Protein Kinase C) isoforms in the differential response of normal and cancer cells to IPC agents. Our results indicate that PKC delta is involved in the enhanced cancer killing, but PKC epsilon is required for the protection of normal cells against oxidative stress.

In summary, our studies indicate for the first time that IPC agents make cancer cells more sensitive to oxidative stress and that the combination of an IPC agent with an oxidizing agent, or compounds that will perturb mitochondrial respiration, could have important therapeutic value. Our novel concept of the effect of IPC agents on cancer cells possess a huge potential to develop individualized therapeutic combinations for different cancers based on the metabolic differences in each cancer cell line.

Citation Format: Shailaja Kesaraju, Arunodoy Sur, Kasirajan Ayyanathan, Herbert Weissbach. Ischemic preconditioning agents sensitize cancer cells to oxidative stress. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A61.