RESUMEN
LSbCl2, an air- and moisture-stable antimony(V)-dipyrrin complex at room temperature, was obtained by treating an excess amount (20 eq.) of SbCl3 with a trianionic N2O2-type tetradentate dipyrrin ligand (L) under visible-light irradiation and O2 atmosphere. The Cl ligands in LSbCl2 were replaced by OH ligands via hydrolysis, yielding LSb(OH)2. Further, the molecular structures and optical properties of the Sb(V)-dippyrin complexes were investigated. While LSbCl2 was non-fluorescent, LSb(OH)2 exhibited an intense red fluorescence with a photoluminescence quantum yield of 68%.
RESUMEN
Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17ß-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERα was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Quinolinas/farmacología , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Citocromo P-450 CYP1A1/metabolismo , Daño del ADN , Células Epiteliales/metabolismo , Estrógenos/farmacología , Femenino , Compuestos Heterocíclicos con 2 Anillos/química , Humanos , Mesodermo/efectos de los fármacos , Mesodermo/metabolismo , Ratones Desnudos , Quinolinas/química , Ratas Desnudas , Receptores de Estrógenos/metabolismo , Transducción de Señal/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genéticaRESUMEN
Effects of toremifene (TOR) in combination with paclitaxel (TXL) on various human breast cancer cell lines were evaluated. TOR and TXL exhibited additive effects on estrogen receptor (ER)-positive cancer cell lines, MCF-7 and T-47D, and a sub-additive effect on a tamoxifen (TAM)-resistant line, T-47D/TAM. To all three ER-negative cancer cell lines, the combined treatment also showed additive effects on MDA-MB-134VI, MDA-MB-231 and MDA-MB-453. Furthermore, a synergistic effect was observed on a multi-drug resistant (MDR) line, Adr. This synergistic effect was more potent in the combination with TOR than that with TAM. The combined treatment increased intracellular TXL, and the accumulation by TOR was 1.5-fold that by TAM. Consequently, the ratio of G2M arrested cells was higher, with statistical significance, in the TOR combination than in the TAM combination. In addition, these synergistic effects in MDR cells were also observed in the combination of TXL with major clinical active metabolites, N-desmethyl-TOR (TOR-1) and 4-hydroxy-TOR (TOR-2). These results suggest that the combination therapy of TOR and TXL might be an effective clinical treatment for breast cancer patients.