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

Pancreatic cancer is a severe malignancy with increasing incidence and high mortality due to late diagnosis and low sensitivity to treatments. Search for the most appropriate drugs and therapeutic regimens is the most promising way to improve the treatment outcomes of the patients. This study aimed to compare (1) in vitro efficacy and (2) in vivo antitumor effects of conventional paclitaxel and the newly synthesized second (SB-T-1216) and third (SB-T-121605 and SB-T-121606) generation taxanes in KRAS wild type BxPC-3 and more aggressive KRAS G12V mutated Paca-44 pancreatic cancer cell line models. In vitro, paclitaxel efficacy was 27.6 ± 1.7 nM, while SB-Ts showed 1.7-7.4 times higher efficacy. Incorporation of SB-T-121605 and SB-T-121606 into in vivo therapeutic regimens containing paclitaxel was effective in suppressing tumor growth in Paca-44 tumor-bearing mice at small doses (≤3 mg/kg). SB-T-121605 and SB-T-121606 in combination with paclitaxel are promising candidates for the next phase of preclinical testing.

• Keywords
• Cancer, Cell biology, Pharmacology,
• Publication type
• Journal Article MeSH

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.

• Keywords
• SB-T taxanes, efficacy, in vitro, in vivo, ovarian carcinoma, paclitaxel, resistance,
• Publication type
• Journal Article 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

Resistance of tumours to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumour uptake of taxanes and their rapid metabolism. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metabolism and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metabolism of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metabolism of the novel taxanes which was therefore not responsible for their different sensitivity, the observed differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G(2)/M block of the cell cycle similar to paclitaxel, but lower at concentrations by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumour cells.

• MeSH
• Cell Culture Techniques MeSH
• Cell Cycle drug effects   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Humans MeSH
• Drug Resistance, Multiple drug effects   MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents * metabolism   pharmacokinetics   pharmacology   MeSH
• Taxoids * metabolism   pharmacokinetics   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Chromatography, High Pressure Liquid MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antineoplastic Agents * MeSH
• Taxoids * MeSH

The study investigated possible mechanisms by which second-generation taxanes, established as significantly more effective than paclitaxel in vitro, suppress a rat lymphoma model in vivo. The studied mechanisms included taxane pharmacokinetics, expression of genes dominating their metabolism (Cyp3a1/2) and transport (Abcb1) and genes controlling tumour angiogenesis (growth factors and receptors). SB-T-1214, SB-T-12854 and IDN5109 suppressed rat lymphoma more effectively than paclitaxel, SB-T-12851, SB-T-12852, SB-T-12853 or IDN5390 as well as P388D1 leukaemia cells in vitro. The greater anti-lymphoma effects of SB-T-1214 in rats corresponded to a higher bioavailability than with SB-T-12854, and lower systemic toxicity of SB-T-1214 for rats reflected its lower cytotoxicity for P388D1 cells in vitro. Suppression of Abcb1 and CYP3a1 expression by SB-T-1214 and IDN5109 could partly explain their anti-lymphoma effects, but not that of SB-T-12854. Growth factors genes Egf, Fgf, Pdgf, and Vegf associated with tumour angiogenesis had significantly lower expression following treatment with anti-lymphoma effective IDN5109 and their receptors were unaffected, whereas inefficient IDN5390 increased expression of the most important Vegf. The effective SB-T-12854 inhibited Egf, Egfr, Fgfr and Pdgfr expression, while the ineffective SB-T-12851, SB-T-12852 and SB-T-12853 inhibited only Egf or Egfr expression. Vegfr expression was inhibited significantly by SB-T-12851 and SB-T-12854, but effect of SB-T-12851 was compromised by induced Vegf expression. The very effective SB-T-1214 decreased the expression of Vegf, Egf and all receptors most prominently indicating the possible supporting role of these genes in anti-lymphoma effects. In conclusion, SB-T-1214, SB-T-12854 and IDN5109 are good candidates for further study.

• MeSH
• Cytochrome P-450 CYP3A genetics   MeSH
• Rats MeSH
• Lymphoma drug therapy   metabolism   pathology   MeSH
• Membrane Proteins genetics   MeSH
• ATP Binding Cassette Transporter, Subfamily B genetics   MeSH
• Neovascularization, Pathologic genetics   MeSH
• Area Under Curve MeSH
• Rats, Sprague-Dawley MeSH
• Antineoplastic Agents blood   pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Taxoids blood   pharmacology   therapeutic use   MeSH
• Tumor Burden drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cyp3a2 protein, rat MeSH Browser
• Cyp3a23-3a1 protein, rat MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• Membrane Proteins MeSH
• multidrug resistance protein 3 MeSH Browser
• ATP Binding Cassette Transporter, Subfamily B MeSH
• Antineoplastic Agents MeSH
• Taxoids MeSH

The aim of this study is to compare the effects of new fluorinated taxanes SB-T-12851, SB-T-12852, SB-T-12853, and SB-T-12854 with those of the classical taxane paclitaxel and novel non-fluorinated taxane SB-T-1216 on cancer cells. Paclitaxel-sensitive MDA-MB-435 and paclitaxel-resistant NCI/ADR-RES human cancer cell lines were used. Cell growth and survival evaluation, colorimetric assessment of caspases activities, flow cytometric analyses of the cell cycle and the assessment of mitochondrial membrane potential, reactive oxygen species (ROS) and the release of cytochrome c from mitochondria were employed. Fluorinated taxanes have similar effects on cell growth and survival. For MDA-MB-435 cells, the C(50) of SB-T-12851, SB-T-12852, SB-T-12853 and SB-T-12854 was 3 nM, 4 nM, 3 nM and 5 nM, respectively. For NCI/ADR-RES cells, the C(50) of SB-T-12851, SB-T-12852, SB-T-12853, and SB-T-12854 was 20 nM, 20 nM, 10 nM and 10 nM, respectively. Selected fluorinated taxanes, SB-T-12853 and SB-T-12854, at the death-inducing concentrations (30 nM for MDA-MB-435 and 300 nM for NCI/ADR-RES) were shown to activate significantly caspase-3, caspase-9, caspase-2 and also slightly caspase-8. Cell death was associated with significant accumulation of cells in the G(2)/M phase. Cytochrome c was not released from mitochondria and other mitochondrial functions were not significantly impaired. The new fluorinated taxanes appear to use the same or similar mechanisms of cell death induction as compared with SB-T-1216 and paclitaxel. New fluorinated and non-fluorinated taxanes are more effective against drug-resistant cancer cells than paclitaxel. Therefore, new generation of taxanes, either non-fluorinated or fluorinated, are excellent candidates for further and detailed studies.

• MeSH
• Cell Death drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Cytochromes c metabolism   MeSH
• DNA, Neoplasm metabolism   MeSH
• Caspases metabolism   MeSH
• Humans MeSH
• Mitochondria drug effects   metabolism   MeSH
• Cell Line, Tumor MeSH
• Paclitaxel chemistry   pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Drug Screening Assays, Antitumor MeSH
• Fluorine Compounds chemistry   pharmacology   MeSH
• Taxoids chemistry   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cytochromes c MeSH
• DNA, Neoplasm MeSH
• Caspases MeSH
• Paclitaxel MeSH
• Reactive Oxygen Species MeSH
• Fluorine Compounds MeSH
• Taxoids MeSH

BACKGROUND: In this study, the effect of novel taxane SB-T-1216 and paclitaxel on sensitive MDA-MB-435 and resistant NCI/ADR-RES human breast cancer cells was compared. MATERIALS AND METHODS: Cell growth and survival were evaluated after 96-hour incubation with tested concentrations of taxanes. The effect on the formation of microtubule bundles was assessed employing fluorescence microscopy and on the cell cycle employing flow cytometric analysis. The activity of caspases was assessed employing commercial colorimetric kits. RESULTS: The IC(50) (concentration resulting in 50% of living cells in comparison with the control) of SB-T-1216 in sensitive cells was 0.6 nM versus 1 nM for paclitaxel. However, the IC(50) of SB-T-1216 in resistant cells was 1.8 nM versus 300 nM for paclitaxel. Both SB-T-1216 and paclitaxel at death-inducing concentrations induced the formation of microtubule bundles in sensitive as well as resistant cells. Cell death induced in sensitive and resistant cells by paclitaxel was associated with the accumulation of cells in the G(2)/M phase. On the contrary, cell death induced by SB-T-1216 took place without the accumulation of cells in the G(2)/M phase but with a decreased number of G(1) cells and the accumulation of hypodiploid cells. Both SB-T-1216 and paclitaxel activated caspase-3, caspase-9, caspase-2 and caspase-8 in sensitive as well as resistant cells. CONCLUSION: Cell death induced by both paclitaxel and novel taxane SB-T-1216 in breast cancer cells is associated with caspase activation and with the formation of interphase microtubule bundles. Novel taxane SB-T-1216, but not paclitaxel, seems to be capable of inducing cell death without the accumulation of cells in the G(2)/M phase.

• MeSH
• Apoptosis drug effects   MeSH
• Cell Division drug effects   MeSH
• Drug Resistance, Neoplasm MeSH
• Doxorubicin pharmacology   MeSH
• Microscopy, Fluorescence MeSH
• Antineoplastic Agents, Phytogenic pharmacology   MeSH
• G1 Phase drug effects   MeSH
• G2 Phase drug effects   MeSH
• Caspase 2 metabolism   MeSH
• Caspase 3 metabolism   MeSH
• Caspase 8 metabolism   MeSH
• Caspase 9 metabolism   MeSH
• Humans MeSH
• Microtubules drug effects   MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms drug therapy   metabolism   pathology   MeSH
• Paclitaxel pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antibiotics, Antineoplastic pharmacology   MeSH
• Taxoids pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Comparative Study MeSH
• Names of Substances
• Doxorubicin MeSH
• Antineoplastic Agents, Phytogenic MeSH
• Caspase 2 MeSH
• Caspase 3 MeSH
• Caspase 8 MeSH
• Caspase 9 MeSH
• Paclitaxel MeSH
• Antibiotics, Antineoplastic MeSH
• Taxoids MeSH