Outcomes for patients with glioblastoma multiforme (GBM) remain poor despite aggressive multimodality therapy. Normal tissue constraints generally preclude further dose escalation with radiation. Therefore, agents that can modify the sensitivity of these tumors to radiation may prove useful clinically in the management of these patients. Curcumin, a major component of tumeric, is used as a spice to give the flavor and yellow coloring to curry. It has been used in traditional medicine for a variety of ailments. Multiple groups have found that curcumin has anti-neoplastic and anti-angiogenic activities. However, while curcumin’s safety is illustrated by its longstanding use in foods, its relatively low potency and poor absorption characteristics limits its clinical development. EF24 and EF31 were developed as synthetic curcumin analogs that display significantly greater potency than the parental compound as anti-cancer agents when screened against a variety of tumor cell lines. We have previously shown that these analogs can function as general kinase inhibitors. Since inappropriate activation of various signal transduction pathways often contribute to resistance to cytotoxic therapies including radiation, we tested whether these agents could radiosensitize glioma cells. We utilized the LN229 glioma cell line that has been engineered to overexpress EGFRvIII (LNvIII), a mutant form of this receptor tyrosine kinase that show constitutive activity and is often seen in GBMs, as well as the corresponding vector control (LNpuro). EF24 (100 nM) and EF31 (10 nM) were used to assess in vitro radiosensitizing activity in the LNpuro and LNvIII cell lines. These drug levels were chosen based on inhibition of growth in the absence of radiation (inhibited clonogenicity by <50%). Both EF24 and EF31 displayed significant radiosensitizing activity by standard clonogenic survival assays. For EF31, dose modifying factors at 10% survival were 1.2 and 1.3 and the SF2 (surviving fraction at 2 Gy) enhancement ratios were 1.3 and 1.6 in LNpuro and LNvIII, respectively. The in vivo radiosensitizing activity of EF31 was next tested in a subcutaneous xenograft model. LNvIII tumors were established in the flanks of nude mice and subjected to treatment +/- EF31 and +/- 12 Gy radiation (3 fractions of 4 Gy given MWF). EF31 (50 mg/kg) was administered daily (approximately 2 hours prior to radiation treatments on MWF) by oral gavage with therapy commencing one day prior to irradiation and continuing for 1 week. While either EF31 or radiation alone only modestly reduced tumor growth, use of EF31 and radiation together further inhibited growth of these tumors in an effect that appeared to be greater than additive. In conclusion, the curcumin analogs can radiosensitize glioma cells both in vitro and in vivo. Further study is warranted for evaluating these agents as adjuncts to radiation therapy for the treatment of GBMs.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA