title: Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells.
abstract: Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC(50) values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer.
authors: Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand. e.leung@auckland.ac.nz
authors: Euphemia
authors: E
authors: Leung
authors: Gordon W
authors: GW
authors: Rewcastle
authors: Wayne R
authors: WR
authors: Joseph
authors: Rhonda J
authors: RJ
authors: Rosengren
authors: Lesley
authors: L
authors: Larsen
authors: Bruce C
authors: BC
authors: Baguley
mesh_terms: D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists; D006801:Humans; D013629:Tamoxifen; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
chemical_list: D003512:Cyclohexanones; D004965:Estrogen Antagonists; D059004:Topoisomerase I Inhibitors; D013629:Tamoxifen; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human