δ-Tocotrienol oxazine derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia

Biomed Res Int. 2014;2014:285752. doi: 10.1155/2014/285752. Epub 2014 Jul 22.

Abstract

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 of δ-tocotrienol and a semisynthetic δ-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated 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 compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in 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 p70S6 kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Hypoxia / drug effects
  • Cell Line, Tumor
  • Cobalt / toxicity
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • Signal Transduction / drug effects
  • Vitamin E / administration & dosage
  • Vitamin E / analogs & derivatives*

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vitamin E
  • tocotrienol, delta
  • Cobalt
  • cobaltous chloride