A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women.

• Klíčová slova
• ABCB1, CpG methylation, MCF-7, TRIP6, breast cancer, cAMP response element, gene amplification,
• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• AMP cyklický MeSH
• chemorezistence * genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádory * genetika   MeSH
• P-glykoproteiny * genetika   MeSH
• proteiny s doménou LIM * genetika   MeSH
• responzivní elementy MeSH
• taxoidy MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• adaptorové proteiny signální transdukční MeSH
• AMP cyklický MeSH
• P-glykoproteiny * MeSH
• proteiny s doménou LIM * MeSH
• taxane MeSH Prohlížeč
• taxoidy MeSH
• transkripční faktory MeSH
• TRIP6 protein, human MeSH Prohlížeč

Taxanes are widely used in the treatment of ovarian carcinomas. One of the main problems with conventional taxanes is the risk of development of multidrug resistance. New-generation synthetic experimental taxoids (Stony Brook Taxanes; SB-T) have shown promising effects against various resistant tumor models. The aim of our study was to compare the in vitro efficacy, intracellular content, and in vivo antitumor effect of clinically used paclitaxel (PTX) and SB-Ts from the previously tested second (SB-T-1214, SB-T-1216) and the newly synthesized third (SB-T-121402, SB-T-121605, and SB-T-121606) generation in PTX resistant ovarian carcinoma cells NCI/ADR-RES. The efficacy of the new SB-Ts was up to 50-times higher compared to PTX in NCI/ADR-RES cells in vitro. SB-T-121605 and SB-T-121606 induced cell cycle arrest in the G2/M phase much more effectively and their intracellular content was 10-15-times higher, when compared to PTX. Incorporation of SB-T-121605 and SB-T-121606 into therapeutic regimens containing PTX were effective in suppressing tumor growth in vivo in NCI/ADR-RES based mice xenografts at small doses (≤3 mg/kg), where their adverse effects were eliminated. In conclusion, new SB-T-121605 and SB-T-121606 analogs are promising candidates for the next phase of preclinical testing of their combination therapy with conventional taxanes in resistant ovarian carcinomas.

• Klíčová slova
• SB-T taxanes, efficacy, in vitro, in vivo, ovarian carcinoma, paclitaxel, resistance,
• Publikační typ
• časopisecké články MeSH