α-Tocopheryloxyacetic acid is superior to α-tocopheryl succinate in suppressing HER2-high breast carcinomas due to its higher stability

Abstract

Breast cancer is the number one neoplastic disease of women, with the HER2-high carcinomas presenting a considerable challenge for efficient treatment. Therefore, a search for novel agents active against this type of cancer is warranted. We tested two vitamin E (VE) analogs, the esterase-hydrolyzable a-tocopheryl succinate (a-TOS) and the non-hydrolyzable ether a-tocopheryloxyacetic acid (a-TEA) for their effects on HER2-positive breast carcinomas using a breast tumor mouse model and breast cancer cell lines. Ultrasound imaging documented that a-TEA suppressed breast carcinomas in the transgenic animals more efficiently than found for its ester counterpart. However, both agents exerted a comparable apoptotic effect on the NeuTL breast cancer cells derived from the FVB/N c-neu mice as well as in the human MBA-MD-453 and MCF7HER2-18 cells with high level of HER2. The superior anti-tumor effect of a-TEA over a-TOS in vivo can be explained by longer persistence of the former in mice, possibly due to the enhanced plasma and hepatic processing of a-TOS in comparison to the esterase-non-cleavable a-TEA. Indeed, the stability of a-TOS in plasma was inferior to that of a-TEA. We propose that a-TEA is a promising drug efficient against breast cancer, as documented by its effect on experimental HER2-positive breast carcinomas that present a considerable problem in cancer management. Breast cancer is a neoplastic disease with very high incidence in women, with a current prediction that one of eight females will develop breast cancer during their lifespan and the trend appears grim.1 Up to 30% of breast cancers can be characterized by high level expression of the receptor tyrosine kinase erbB2 (HER2), which seriously complicates the treatment of such neoplasias due to enhanced proliferative status and resistance to apoptosis.2-4 The most frequently used therapeutics for HER2-positive breast cancer is the humanized antibody Herceptin (trastuzumab), often in combination with chemotherapeutic agents.5 Although this approach has been applied with some success, Herceptin is a serious economical burden and, more importantly, exerts severe cardiotoxic side-effects.6, 7 Mitocans, drugs with anti-cancer activity acting via mitochondrial destabilization, often causing early generation of reactive oxygen species (ROS), have been a recent focus of research.8-10 We and others have been developing novel anti-cancer drugs from the group of vitamin E (VE), epitomized by the redox-silent a-tocopheryl succinate (a-TOS).11-15 These agents have been shown to be efficient against a range of cancer types,16 including HER2-positive breast tumors, as documented in studies with a-TOS and breast cancer cell lines with high level of HER2 as well as transgenic mice with spontaneous HER2-positive carcinomas.17, 18 One problem with esters like a-TOS is that they are vulnerable to esterases,19 making their stability/retention in the system relatively low, potentially jeopardizing their clinical application. This problem may be potentially overcome by using a recently synthesized analog of a-TOS, the ether a-tocopheryloxyacetic acid (a-TEA) that is resistant to esterase attack.20 Encouragingly, the ether VE analog has been shown to suppress breast cancer in a syngeneic mouse model.21, 22