δ-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia

In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role ofδ-tocotrienol and a semisyntheticδ-tocotrienol oxazine derivative, compound44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1αlevels, and combined treatment with compound44attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound44blocked this response. Additionalin vivostudies showed that intralesional treatment with compound44in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with theδ-tocotrienol oxazine derivative, compound44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors.