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- W2968759260 abstract "4017 We have previously shown that the epidermal growth factor-receptor (EGFR) tyrosine kinase inhibitor PD153035 induces retinoic acid receptor(RAR)-beta expression in breast and ovarian cancer cells by mechanisms that are independent of its blocking activity on EGFR (ErbB1) or on any other ErbB receptor (ErbB2, ErbB3, ErbB4). RAR-beta2, one of three human RAR-beta isoforms (RAR-beta1, RAR-beta2, RAR-beta4), is silenced in many tumors and acts as a tumor suppressor. Forced expression of RAR-beta2 reverts the malignant phenotype of RAR-beta2-negative breast cancer cells and reconstitutes retinoid sensitivity in these cells. Here we demonstrate that the EGFR inhibitor PD153035 specifically induces RAR-beta2, but not the other two isoforms (RAR-beta1, RAR-beta4) in human breast (MDA-MB-468, MDA-MB-453) cancer cells. Induction was seen at the mRNA (RT-PCR) and protein level (Western analysis). PD153035-mediated induction of RAR-beta2 was associated with synergistic growth inhibition in cells co-treated with PD153035 and all-trans retinoic acid (tRA). Most importantly, PD153035 restored retinoid sensitivity in retinoid resistant cells. Our previous work also revealed that PD153035 directly intercalates into the DNA double helix suggesting that changes in the chromatin structure contribute to the RAR-beta inducing effect of PD153035. This prompted us to examine the effect of classical DNA intercalating chemotherapeutic drugs such as doxorubicin, amsacrine and mitoxantrone on the expression of RAR-beta. Vincristine was used for comparative reasons, since this cytotoxic drug does not target the DNA. All four compounds caused dose-dependent growth inhibition in MDA-MB-468 and MDA-MB-453 cells. Interestingly, compounds that directly interact with the DNA double helix (doxorubicin, amsacrine, mitoxantrone) caused a time-dependent upregulation of the RAR-beta expression in all cell lines examined, whereas the negative control drug vincristine, which causes disassembly of microtubule structures, did not stimulate RAR-beta expression. This data further supports the notion that induction of the RAR-beta tumor suppressor gene in cancer cells by PD153035 is mediated at least in part by its DNA intercalating activity." @default.
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- W2968759260 date "2007-05-01" @default.
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- W2968759260 title "There is more to some EGF receptor inhibitors - PD153035 reveals triple action: EGF receptor inhibition, DNA-intercalation, RAR-beta induction" @default.
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