Vitamin E Analog α-TEA and Celecoxib Alone and Together Reduce Human MDA-MB-435-FL-GFP Breast Cancer Burden and Metastasis in Nude Mice

Abstract

Alpha-TEA, a nonhydrolyzable ether analog of vitamin E (RRR-alpha-tocopherol), and celecoxib, a specific COX-2 inhibitor, were delivered separately or in combination to investigate their anticancer properties, using MDA-MB-435-FL-GFP human breast cancer xenografts in nude mice. Liposomal formulated alpha-TEA administered as an aerosol and celecoxib fed at 500 or 1250 mg/kg diet for 31 days separately or in combination significantly reduced tumor volume in comparison to control (p < 0.001 for all treatment groups). Of special note, the combinations of alpha-TEA + celecoxib (1250) inhibited tumor volume significantly better than either single treatment (p < 0.001 and p < 0.001). Average number of macroscopic lung metastases were significantly reduced in all treatment groups in comparison to control, with the exception of celecoxib (500). Mean numbers of microscopic lung and lymph node metastases in all treatment groups were significantly lower than control. Furthermore, the mean number of microscopic lung metastases in the alpha-TEA+celecoxib (1250) group were significantly lower than either separate treatment. Analyses of 5 microm tumor sections showed that all treatments, with the exception of celecoxib (500) alone, significantly enhanced apoptosis (TUNEL) and significantly decreased cell proliferation (Ki-67). alpha-TEA and alpha-TEA + celecoxib (1250) treatments significantly reduced blood vessel density (CD-31) in comparison to control. These data show promise for combination alpha-TEA + celecoxib chemotherapy for breast cancer.

COX-2 involvement in breast cancer metastasis to bone

“…With the use of other pre-clinical models, others have shown that a COX-2 inhibitor celecoxib inhibits angiogenesis and induces apoptosis in breast cancer cells in a mouse model of spontaneous metastasis (Basu et al, 2004). In another model involving MDA-435-FL-GFP human breast cancer xenografts in nude mice, Zhang et al (2004) showed that celecoxib inhibits overall tumor burden and lung metastasis. COX-2 could have yet additional roles including a role in the pre-malignant phenotype (Crawford et al, 2004) and a role in suppressing tumor-specific host immune responses (Kundu et al, 2005;Basu et al, 2006).…”

α-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells

“…Unlike RRR-α-tocopherol, α-TEA is not an antioxidant and it exhibits potent antitumor activity both in vivo and in vitro [4][5][6][7][8][9][10]. α-TEA has been shown to exhibit both antitumor and antimetastatic activity in animal xenograft and syngeneic mouse models of breast cancer when administered by aerosol and if formulated properly when administered orally, suggesting a possible therapeutic potential [4][5][6][7]. α-TEA is noteworthy not only for its ability to reduce tumor burden and metastases in vivo but also for its lack of toxicity toward normal cells and tissues in these animal models [4][5][6][7]11].…”

On the Existence of Cellular Tocopheryl Phosphate, its Synthesis, Degradation and Cellular Roles: A Hypothesis

“…Furthermore, tocopheryl succinate and even more tocopheryl maleate (12) or the non-hydrolysable ether analog of a-tocopherol, a-TEA (2,5,7,8-tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid) (13) have been shown to have cell properties far stronger than a-tocopherol. As working hypothesis it can be suggested that the nonhydrolysable tocopheryl succinate and tocopheryl maleate may mimic and substitute for TP causing a permanent activation of cellular signals.…”