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.

• Klíčová slova
• Cancer, Cell biology, Pharmacology,
• Publikační typ
• časopisecké články 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.

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

• Klíčová slova
• ABCC3, CPS1, Stony Brook taxanes, TRIP6, multidrug resistance, ovarian carcinoma, taxanes,
• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• chemorezistence genetika   MeSH
• down regulace účinky léků   genetika   MeSH
• epiteliální ovariální karcinom farmakoterapie   genetika   MeSH
• karbamoylfosfátsynthasa (amoniak) genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové biomarkery genetika   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků farmakoterapie   genetika   MeSH
• paclitaxel terapeutické užití   MeSH
• proteiny s doménou LIM genetika   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• taxoidy terapeutické užití   MeSH
• transkripční faktory genetika   MeSH
• viabilita buněk účinky léků   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• CPS1 protein, human MeSH Prohlížeč
• karbamoylfosfátsynthasa (amoniak) MeSH
• multidrug resistance-associated protein 3 MeSH Prohlížeč
• nádorové biomarkery MeSH
• paclitaxel MeSH
• proteiny s doménou LIM MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• taxoidy MeSH
• transkripční faktory MeSH
• TRIP6 protein, human MeSH Prohlížeč