Investigation of the effects of [alpha]-TEA, 9-nitrocamptothecin and paclitaxel alone and in combination on 66cl-4-GFP murine mammary cancer cells in vitro and in vivo

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Latimer, Paul Brian, 1976-

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Second only to lung cancer, breast is the leading type of cancer among women in the US. Despite all the medical advances over the past few decades, toxicity and increased resistance to standard drug therapy still remains a significant problem. The heterogeneic nature of all cancers has led to a shift in treatment approaches, in that more research is being carried out with combination treatments in the hope that a multidirectional targeting of cancer will be far more effective than the current single treatment options. Our goal was to gain a better understanding of the molecular mechanisms of a nonhydrolyzable ether analog of RRR-[alpha]-tocopherol, 2, 5, 7, 8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (abbreviated [alpha] -TEA), and to investigate its efficacy when used in combination with known chemotherapeutics 9-nitro-camptothecin (9NC), and Paclitaxel (Taxol). The data presented here looks encouraging as it shows a clinically relevant delivery method using [alpha]-TEA and 9NC has the unique ability to reduce primary tumor burden as well as macro and micrometastatic lung and lymph node lesions in an aggressive syngeneic mouse mammary model, while displaying no obvious toxic side effects. The effect of combination treatments on tumor volume appears in part to be moderated by an increase in tumor cell apoptosis and a decrease in tumor cellular proliferation. Next, the intricate molecular mechanism of how [alpha]-TEA alone and in combination with 9NC is able to induce apoptosis in 66cl-4-GFP murine mammary cancer was investigated. The data suggest that the signaling pathway that ultimately leads to apoptosis is caspase dependent, is able to upregulate pro-death players while at the same time downregulate pro-survival proteins such as c-Flip and survivin. Finally, we investigated the efficacy of [alpha]-TEA used in an allograft mouse model following treatment with Taxol. Combination treatments were able to significantly reduce primary tumor burden, decrease lung and lymph node micrometastases, tumor cell proliferation, tumor blood vessel density as well as increase tumor cell apoptosis. Based on the results presented, we propose that [alpha]-TEA when used alone and in combination is an effective, non-toxic option for cancer treatment which warrants further investigation.