ATPS-06BRAIN-PENETRANT ALKYLINDOLE COMPOUNDS PROMOTE APOPTOSIS IN GLIOMA CELLS THROUGH MICROTUBULE DESTABILIZATION

Glioblastoma multiforme (GBM) is the most common and aggressive brain neoplasm. Treatment options for this cancer are limited, and the five-year survival rate is less than 5%. Cannabinoid compounds have the ability to cross the blood brain barrier (BBB) and selectively kill tumor cells while maintaining a favorable safety profile, making them attractive candidates as novel GBM therapeutics. For example, the cannabinoid agonists WIN55212-2 (WIN-2) and Δ9-tetrahydrocannabinol (THC) induce GBM cell death both in vitro and reduce tumor growth in vivo, while sparing healthy cells. While cannabinoid compounds typically act through two G protein-coupled receptors (GPCR), CB1, and CB2, evidence suggests that WIN-2, an alkylindole (AI) cannabinoid, kills tumor cells through a separate, unknown mechanism. To explore this unknown mechanism, our lab developed a novel series of AI compounds that exhibit reduced affinity to CB1 and CB2 receptors. The model AI compound, ST-11, was found to destabilize microtubules (MTs) and promote both cell cycle arrest in prometaphase and caspase-dependent apoptosis. Recent studies have shown that GBMs are particularly sensitive to mitotic disruption; however, the use of MT-targeting agents is limited by toxic side effects and a general inability to cross the BBB. ST-11 was found to exhibit a promising safety profile in mice and did not induce overt toxicity in any major organs up to its maximal administrable dose of 240 mg/kg. Additionally, ST-11 readily crossed the BBB within 60 min of intraperitoneal injection and dose-dependently induced caspase activation and reduced tumor size in an orthotopic syngeneic glioma mouse model. Our findings suggest that AI compounds such as ST-11 belong to a new class of brain-penetrant MT-targeting agents that preferentially kill tumor cells.