Hypoxic regions found in most solid tumors often contain cells which are resistant to various cancer therapies. However, hypoxia also forces cells to rely mainly on the catabolism of glucose through glycolysis for ATP production and survival, and thereby creates a therapeutic window that can be exploited by glycolytic inhibitors, i.e. 2-deoxyglucose (2-DG). Previously we reported that 2-DG is toxic to tumor cells growing in vitro under hypoxic conditions. Moreover, it was found that when hypoxia inducible factor (HIF-1) was attenuated using siRNA directed against this transcription factor in cells growing under hypoxia, sensitivity to 2-DG increased. Since HIF-1α translation is regulated by the major translational controller, mammalian target of rapamycin (mTOR), we examined the effects of blocking mTOR with a water soluble analog of rapamycin (CCI-779) and found that HIF-1α was down-regulated which coincided with increased sensitivity to 2-DG. A significant increase in trypan blue positive cells (indicating death) was observed when CCI-779 was combined with 2-DG as compared to 2-DG alone in the small cell lung cancer line, SCLCB, growing under hypoxic conditions for 72 hrs. At 6 and 8mM of 2-DG, 45 and 60% of these cells were dead while when combined with a non-toxic dose of CCI-779 (0.1µg/ml) cell death increased to 80 and 90% respectively. In addition, using HIF+ (Hepa-1) and HIF- (C4) cell lines growing under hypoxia, we found that in the C4 line, CCI-779 did not increase the toxicity of 2-DG whereas in the Hepa-1 cell line it did. Although blockage of mTOR leads to numerous downstream consequences, the fact that it did not increase 2-DG sensitivity in the HIF- cell line indicates that HIF is responsible for a level of resistance to 2-DG. Since CCI-779 is currently under clinical trials (Phase III), its activity in inhibiting HIF may prove to be beneficial to patients when combined with 2-DG, which is also in clinical trials (Phase I).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA