These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.
Pubmed for Handhelds
PUBMED FOR HANDHELDS
Search MEDLINE/PubMed
Title: The DNA-binding epidermal growth factor-receptor inhibitor PD153035 and other DNA-intercalating cytotoxic drugs reactivate the expression of the retinoic acid receptor-beta tumor-suppressor gene in breast cancer cells. Author: Grunt TW, Tomek K, Wagner R, Puckmair K, Zielinski CC. Journal: Differentiation; 2007 Nov; 75(9):883-90. PubMed ID: 17608728. Abstract: We have previously shown that the epidermal growth factor-receptor (EGFR) tyrosine kinase inhibitor PD153035 induces retinoic acid receptor-beta (RAR-beta) expression in malignant 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 MDA-MB-468 and MDA-MB-453 human breast cancer cells. Induction was seen at the mRNA (reverse transcription-polymerase chain reaction) 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 retinoic acid sensitivity in retinoic acid-resistant cells. Our previous work also revealed that PD153035 directly intercalates into the DNA suggesting that changes in the chromatin structure contribute to the RAR-beta2-inducing effect of PD153035. This prompted us to examine the effect of DNA intercalating chemotherapeutic drugs such as doxorubicin, amsacrine, and mitoxantrone on the expression of RAR-beta. Vincristine was used for comparative reasons, because this drug does not target 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 (doxorubicin, amsacrine, mitoxantrone) caused a time-dependent up-regulation of the RAR-beta expression in all cell lines examined, whereas the negative control drug vincristine, which causes disruption of microtubule structures, did not stimulate RAR-beta expression. These data further support 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.[Abstract] [Full Text] [Related] [New Search]