Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells

Abstract

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.

Differentially expressed proteins in human MCF-7 breast cancer cells sensitive and resistant to paclitaxel

“…The cells were cultured in a medium based on the RPMI 1640 (Sigma-Aldrich, St. Louis, MO, USA) containing phenol red, extra L-glutamine (300 μg/ml), sodium pyruvate (110 μg/ml), HEPES (15 mM), penicillin (100 U/ml) and streptomycin (100 μg/ml), as previously described [29,30]. The medium was also supplemented with 10% heat-inactivated fetal bovine serum (Biochrom AG, Berlin, Germany).…”

Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies

“…The metabolic stability of 3′-difluorovinyltaxoids against P-450 family enzymes was examined and it was found that almost no appreciable metabolites were formed [49]. The results indicate that not only the metabolism at C3′ is effectively blocked, but also oxidative metabolism is suppressed on other parts of the taxoid molecule, including the C3′N- t -Boc and C6 methylene moieties [49], which are known to be the major metabolism sites for docetaxel and paclitaxel [50–52].…”

“…The results indicate that not only the metabolism at C3′ is effectively blocked, but also oxidative metabolism is suppressed on other parts of the taxoid molecule, including the C3′N- t -Boc and C6 methylene moieties [49], which are known to be the major metabolism sites for docetaxel and paclitaxel [50–52]. Consequently, our strategic incorporation of a difluorovinyl group in place of an isobutenyl group at C3′ has been proven to be successful in blocking the major metabolism of the isobutenyl moiety in the new-generation taxoids (see Fig.…”

Fluorine-containing taxoid anticancer agents and their tumor-targeted drug delivery

“…In our recent study on the metabolic stability of difluorovinyltaxoids against P-450 family enzymes, almost no appreciable metabolites were detected [30]. The results suggests that not only the metabolism at C3′ is effectively blocked, but also oxidative metabolism on other parts of the taxoid molecule, including the C3′N- t -Boc and C6 methylene moieties, which are major metabolism sites for docetaxel and paclitaxel [31–33], is suppressed [30].…”

“…The results suggests that not only the metabolism at C3′ is effectively blocked, but also oxidative metabolism on other parts of the taxoid molecule, including the C3′N- t -Boc and C6 methylene moieties, which are major metabolism sites for docetaxel and paclitaxel [31–33], is suppressed [30]. Thus, our strategic incorporation of a difluorovinyl group in place of an isobutenyl group at C3′ has been proven to be successful in blocking the observed metabolism of the isobutenyl moiety in 2 nd -generation taxoids (see Fig.…”