We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.

• Keywords
• C10 taxane derivatives, C2 taxane derivatives, C3´ and C3´N taxane derivatives, Resistant breast cancer cells, Resistant ovarian cancer cells,
• MeSH
• Benzoates pharmacology   chemistry   MeSH
• Drug Resistance, Neoplasm * drug effects   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms drug therapy   pathology   MeSH
• Ovarian Neoplasms drug therapy   pathology   MeSH
• ATP Binding Cassette Transporter, Subfamily B * metabolism   genetics   MeSH
• Paclitaxel pharmacology   MeSH
• Antineoplastic Agents pharmacology   chemistry   MeSH
• Taxoids pharmacology   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• ABCB1 protein, human MeSH Browser
• Benzoates MeSH
• ATP Binding Cassette Transporter, Subfamily B * MeSH
• Paclitaxel MeSH
• Antineoplastic Agents MeSH
• Taxoids MeSH

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.

• Keywords
• ABCB1, CpG methylation, MCF-7, TRIP6, breast cancer, cAMP response element, gene amplification,
• MeSH
• Adaptor Proteins, Signal Transducing genetics   MeSH
• Cyclic AMP MeSH
• Drug Resistance, Neoplasm * genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Neoplasms * genetics   MeSH
• ATP Binding Cassette Transporter, Subfamily B * genetics   MeSH
• LIM Domain Proteins * genetics   MeSH
• Response Elements MeSH
• Taxoids MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• ABCB1 protein, human MeSH Browser
• Adaptor Proteins, Signal Transducing MeSH
• Cyclic AMP MeSH
• ATP Binding Cassette Transporter, Subfamily B * MeSH
• LIM Domain Proteins * MeSH
• taxane MeSH Browser
• Taxoids MeSH
• Transcription Factors MeSH
• TRIP6 protein, human MeSH Browser

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Doxorubicin pharmacology   MeSH
• Ketones pharmacology   MeSH
• Humans MeSH
• Drug Resistance, Multiple MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Doxorubicin MeSH
• Ketones MeSH
• Antineoplastic Agents * MeSH

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

• Keywords
• ABCC3, CPS1, Stony Brook taxanes, TRIP6, multidrug resistance, ovarian carcinoma, taxanes,
• MeSH
• Adaptor Proteins, Signal Transducing genetics   MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Down-Regulation drug effects   genetics   MeSH
• Carcinoma, Ovarian Epithelial drug therapy   genetics   MeSH
• Carbamoyl-Phosphate Synthase (Ammonia) genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mice, Nude MeSH
• Mice MeSH
• Biomarkers, Tumor genetics   MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms drug therapy   genetics   MeSH
• Paclitaxel therapeutic use   MeSH
• LIM Domain Proteins genetics   MeSH
• Multidrug Resistance-Associated Proteins genetics   MeSH
• Taxoids therapeutic use   MeSH
• Transcription Factors genetics   MeSH
• Cell Survival drug effects   genetics   MeSH
• Animals MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• CPS1 protein, human MeSH Browser
• Carbamoyl-Phosphate Synthase (Ammonia) MeSH
• multidrug resistance-associated protein 3 MeSH Browser
• Biomarkers, Tumor MeSH
• Paclitaxel MeSH
• LIM Domain Proteins MeSH
• Multidrug Resistance-Associated Proteins MeSH
• Taxoids MeSH
• Transcription Factors MeSH
• TRIP6 protein, human MeSH Browser