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

Abstract

BackgroundHER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity.MethodsIn 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.ResultsWe 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.ConclusionDue 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.

The Role of Alpha Tocopheryl Succinate (α-TOS) as a Potential Anticancer Agent

“…This result has also been observed in xenograft models using immune compromised mice transplanted with human ovarian, breast, or prostate cancer cells and in spontaneous breast cancer models (12,14,38). Cell culture studies have shown that α-TEA induces human ovarian, prostate, and breast cancer cells to undergo DNA synthesis arrest and apoptosis and that α-TEA-induced apoptosis involves activation of Fas/Fas ligand and c-Jun NH2-terminal kinase (JNK) proapoptotic pathways, as well as suppression of Akt, FLIP, and surviving anti-apoptotic/pro-survival factors (16).…”

“…One limitation to treatment with α-TOS is its vulnerability to esterases, complicating its oral use (12,13). Recently, an analog of α-TOS that is resistant to esterase attack, α-TEA, was synthesized and has been shown to suppress human carcinoma cells in several experimental models (12,(14)(15)(16). α-TEA has an acetic acid 168 A. ANGULO-MOLINA ET AL.…”

“…Cell culture studies have shown that α-TEA induces human ovarian, prostate, and breast cancer cells to undergo DNA synthesis arrest and apoptosis and that α-TEA-induced apoptosis involves activation of Fas/Fas ligand and c-Jun NH2-terminal kinase (JNK) proapoptotic pathways, as well as suppression of Akt, FLIP, and surviving anti-apoptotic/pro-survival factors (16). Recently, it was reported that in addition to its direct cytotoxic effects and antitumor effect, α-TEA treatment may activate the immune response (14,17). Table 1 summarizes the most recent experiments evaluating growth inhibition and increases in survival using animal models; in most of them apoptosis of cancer cells was the principal effect of α-TEA treatment.…”

Targeting HER2 Positive Breast Cancer with Chemopreventive Agents

“…Recent studies with alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, suppressed mammary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer (114). Another group showed that α-Tocopheryl succinate (α-TOS) was capable of inducing apoptosis in HER2 low and HER2+ cells, suggesting that α-TOS could potentially overcome the pro-survival effects of HER2+ breast cancers (115).…”

The role of antioxidants in the era of cardio-oncology

“…This has been considered strong evidence indicating that ROS accumulation and oxidative stress is not the major mechanism by which anthracyclines kill cancer cells. Despite reports that the inhibition of ErbB2 produces ROS in cancer cells (Dogan et al, 2011; Aird et al, 2012), the use of antioxidants during trastuzumab therapy may be supported by the observations that a vitamin E analog can enhance the antitumor activity of trastuzumab (Hahn et al, 2011). …”