Investigation of the effect of a novel vitamin E derivative (alpha-TEA) alone and in combination with a known chemotherapuetic agent in human breast cancer using cell culture and animal models

Abstract

Several studies have described the potent anti-tumor activity of RRR-α- tocopheryl succinate (vitamin E succinate; VES), a hydrolyzable ester derivative of RRR- α-tocopherol (natural vitamin E), demonstrating that VES is a potent growth inhibitor of a wide variety of epithelial cancer cell types, including breast, prostate, lung, and colon; as well as, hematopoietic-lymphoid leukemia and lymphoma cells, in vitro, and exert these effects via induction of apoptosis, inhibition of DNA synthesis, and induction of cellular differentiation. Recent studies have demonstrated VES to have anti-tumor and anti-metastatic activity in animal xenograft and allograft models when administered intraperitoneally (i.p.), but not when delivered orally, suggesting a possible route specific therapeutic potential. In an effort to develop a clinically useful vitamin E-based chemotherapeutic agent and to administer it in a clinically-relevant manner, a nonhydrolyzable ether analog of RRR-α-tocopherol; namely, 2,5,7,8-tetramethyl-2R-(4R, 8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (called RRR-α-tocopheryloxyacetic acid or RRR-α-tocopherol ether-linked acetic acid analog; and abbreviated α-TEA) has been produced. Data reported here are promising in that they show that a novel vitamin E analog exhibits the ability to decrease primary tumor burden and reduce lung and lymph node metastasis in a rather rapid and aggressive syngeneic tumor model without any overt toxic effects when administered by clinically relevant routes; namely, aerosol and oral delivery. Increased rates of tumor cell apoptosis and inhibition of cell proliferation in tumors of animals treated with α-TEA, imply that the anti-tumor effect is due, at least in part, to analog triggering of tumor cell death and inhibition of cell proliferation. The mechanism of how α-TEA reduces lung metastasis in this model system is unknown and warrants further investigation, but is unlikely due to a decrease in angiogenesis. In addition, combinations of this vitamin E derivative with 9-nitrocamptothecin (9-NC), a camptothecin derivative used in the treatment of ovarian and pancreatic cancers, show an enhanced effect on the decrease in tumor burden in this model.