Selective Retinoids That Inhibit IKK as Chemotherapeutic Agents Against Estrogen-Independent Breast Cancer Cells
Annual rept. 16 Jul 2002-15 Jul 2002
SIDNEY KIMMEL CANCER CENTER SAN DIEGO CA
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We have investigated the effect of novel selective retinoid-related molecules that induce apoptosis in breast cancer cells on IKKNF kappa B activity. We identified one retinoid antagonist that elicited a strong inhibition of IKK in the ER-negative cell line MDA-MB-468. Other retinoid analogs were not as potent IKK inhibitors in intact cells, although they exerted a significant inhibition of IKK in vitro and a strong inhibition of cell proliferation that correlated with the induction of apoptosis in ER-negative cells. Our data observed in breast cancer cells as well as in cells obtained from other type of human tumors indicate that the inhibition of IKKNF kappa B activity is critical for the induction of apoptosis by the retinoid antagonist, but not by other retinoid analogs. Our findings with non-retinoid analogs known to inhibit IKK and a non- pharmacological approach to block IKKNF kappa B signaling, indicate that inhibition of this pathway is sufficient to induce cell death. Therefore, inhibitors of IKK could serve as promising new anticancer agents, either as a stand-alone therapy or in combination therapies with other anticancer approaches. In this respect, it is noteworthy that inhibitors of IKK sensitize tumor cells to the anticancer activity of certain chemotherapeutic drugs.
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