Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors.
Taxanes antitumour agents such as paclitaxel and docetaxel represent a successful family of chemotherapeutic drugs. Unfortunately, acquired and innate resistance represents a clinical problem for these drugs. We investigated, on a panel of 7 human cancer cell lines, the growth inhibition effect of 3 newly developed taxanes (SB-T-1213, SB-T-1250 and SB-T-101187) with modification at the C10 and C3' positions of the taxane framework. These positions have been previously characterized as critical to make taxanes highly active against cells overexpressing the efflux pump P-glycoprotein (P-gp). Paclitaxel and docetaxel were used as reference compounds. Results unambiguously indicate the exceptional activity of the novel taxanes toward P-gp positive cells (up to >400 fold higher potency than that of paclitaxel). SB-T-1213 and SB-T-1250 are also substantially more active than the reference compounds against P-gp negative cells. To better understand the mechanisms underlying the enhanced activity of the newly developed taxanes, we performed cell cycle and apoptosis analysis. This study demonstrates that the striking growth inhibition effect exhibited by the novel taxanes is ascribed to their increased ability in inducing apoptosis and G(2)/M cell cycle block. SB-T-1213 and SB-T-1250 are also more active than reference compounds in inducing intracellular accumulation of the beta-tubulin subunits. Finally, it is revealed that these novel taxanes have ability to inhibit the function of the P-gp efflux pump on the basis of the Rhodamine 123 assay. These findings strongly suggest that SB-T-1213, SB-T-1250 and SB-T-101187 represent a new tool to overcome innate or acquired P-gp mediated taxane-resistance.
Ferlini
C
C
Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynaecology, Università Cattolica Sacro Cuore, Rome, Italy.
Distefano
M
M
Pignatelli
F
F
Lin
S
S
Riva
A
A
Bombardelli
E
E
Mancuso
S
S
Ojima
I
I
Scambia
G
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids; D014404:Tubulin / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C418631:SB T-101187; C101718:SB T-1213; C418630:SB T-1250; D043823:Taxoids; D014404:Tubulin; C080625:taxane; D017239:Paclitaxel