Investigation of the effects and mechanisms of action of a novel vitamin E derivative (alpha-TEA) in combination with Cisplatin, and the resulting reversal of drug resistance in a Cisplatin-resistant human ovarian cancer cell line, Cp70

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Anderson, Kristen Marie

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RRR-α-tocopheryl succinate (VES) and vitamin E analog [2,5,7,8-tetramethyl- 2R-(4R,8R-12-trimethyltridecyl)chroman-6-yloxy] acetic acid (α-TEA) induce human breast, prostate, lung, colon, cervical, and endometrial tumor cells in culture to undergo apoptosis. An exception is the human ovarian cancer cell line A2780, and its cisplatin- resistant subclone A2780/cp70 (cp70). These cells are responsive to the induction of apoptosis by α-TEA, but not VES. Evidence in these studies indicate that differences in the structural integrity (stability) of the ester linked succinate moiety of VES versus the ether linked acetic acid moiety of α-TEA explains, in part, why cp70 cells respond differently to the induction of apoptosis by the two compounds. Data suggest that the failure of VES to induce cp70 cells to undergo apoptosis is due to cellular esterases that convert VES to RRR-α-tocopherol, removing its anti-tumor activity. The ether linkage of α-TEA is not hydrolysed in these cells. Thus, due to its stability, the α-TEA molecule shows more promise not only in these cell lines in culture, but also as a more clinically relevant chemotherapeutic agent. In addition, combination treatments of α-TEA with cisplatin induced high levels of apoptosis in both A2780 and cisplatin-resistant cp70 cells. Evidence indicates a synergistic relationship between these two compounds in this ovarian cancer cell line, as α-TEA restores signaling through MAP kinase pathways that have been lost in the acquisition of cisplatin resistance. Preliminary in vivo data support these in vitro results confirming the efficacy of combination therapy. Co-treatment of α-TEA administered via aerosol with cisplatin treatment via intraperitoneal injection reduces tumor burden and metastasis to lungs and lymph nodes in a nude mouse xenograft model of the cp70 cisplatin-resistant cell line.



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