The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer

In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo.We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone.Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody.Alpha-tocopheryloxyacetic acid (α-TEA) is an ether derivative of naturally occurring vitamin E (alpha-tocopherol). Unlike vitamin E, which lacks in vivo anti-tumor activity and fails to prevent cancer in humans [1,2], α-TEA is directly cytotoxic to tumor cells [3-7] via a mechanism that includes mitochondrial depolarization and generation of reactive oxygen species leading to apoptotic cell death [8-10] as has been reported for alpha-tocopheryl succinate (α-TOS) [11]. Unlike alpha-tocopheryl succinate (α-TOS), which is susceptible to conversion to the apoptosis-inert tocopherol and succinic acid by intestinal esterases, α-TEA is stable and induces apoptosis of a variety of mouse and human cancer cell lines while sparing normal cells [3,4,6,7]. More importantly, we reported recently that oral α-TEA significantly inhibited the growth of transplanted murine breast cancer (4T1) and dramatically reduced the incidence of lung metastases [7] and was able to suppress growth in a clinically relevant spontaneous model of breast cancer (MMTV-PyMT) without overt toxicity [6].HER2/neu is a proto-oncoge