TY - JOUR
T1 - Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of β-Tubulin and the Multidrug Resistance Associated P-Glycoprotein
AU - Yang, Chia Ping Huang
AU - Wang, Changwei
AU - Ojima, Iwao
AU - Horwitz, Susan Band
N1 - Funding Information:
The authors thank Dr. L. Samaraweera for helpful discussions. This work was supported by the Breast Cancer Research Foundation, the National Foundation for Cancer Research, NCI grants CA077263 and CA103314, and the Albert Einstein Cancer Center Support Grant of the NIH award P30CA013330.
Publisher Copyright:
© 2018 American Chemical Society and American Society of Pharmacognosy.
PY - 2018/3/23
Y1 - 2018/3/23
N2 - Several next-generation taxanes have been reported to possess high potency against Taxol-resistant cancer cell lines overexpressing βIII-tubulin and/or P-glycoprotein (P-gp), both of which are involved in drug resistance. Using a photoaffinity Taxol analogue, 2-(m-azidobenzoyl)taxol, two potent next-generation taxanes, SB-T-1214 and SB-CST-10202, exhibited distinct inhibitory effects on photolabeling of β-tubulin from different eukaryotic sources that differ in β-tubulin isotype composition. They also specifically inhibited photolabeling of P-gp, and the inhibitory effect correlated well with the steady-state accumulation of [ 3 H]vinblastine in a multidrug resistant (MDR) cell line, SKVLB1. Several microtubule-stabilizing agents (MSAs)-resistant cell lines from the human ovarian cancer cell line Hey were isolated, and their MDR1 and βIII-tubulin levels determined. Distinct potencies of the two taxanes against different MSA-resistant cells expressing unique levels of MDR1 and βIII-tubulin were found. Cytotoxicity assays, done in the presence of verapamil, indicated that SB-T-1214 is a substrate, although not as good as Taxol, for P-gp. The mechanisms involved in drug resistance are multifactorial, and the effectiveness of new Taxol analogues depends on the interaction between the drugs and all possible targets; in this case the two major cellular targets are β-tubulin and P-gp.
AB - Several next-generation taxanes have been reported to possess high potency against Taxol-resistant cancer cell lines overexpressing βIII-tubulin and/or P-glycoprotein (P-gp), both of which are involved in drug resistance. Using a photoaffinity Taxol analogue, 2-(m-azidobenzoyl)taxol, two potent next-generation taxanes, SB-T-1214 and SB-CST-10202, exhibited distinct inhibitory effects on photolabeling of β-tubulin from different eukaryotic sources that differ in β-tubulin isotype composition. They also specifically inhibited photolabeling of P-gp, and the inhibitory effect correlated well with the steady-state accumulation of [ 3 H]vinblastine in a multidrug resistant (MDR) cell line, SKVLB1. Several microtubule-stabilizing agents (MSAs)-resistant cell lines from the human ovarian cancer cell line Hey were isolated, and their MDR1 and βIII-tubulin levels determined. Distinct potencies of the two taxanes against different MSA-resistant cells expressing unique levels of MDR1 and βIII-tubulin were found. Cytotoxicity assays, done in the presence of verapamil, indicated that SB-T-1214 is a substrate, although not as good as Taxol, for P-gp. The mechanisms involved in drug resistance are multifactorial, and the effectiveness of new Taxol analogues depends on the interaction between the drugs and all possible targets; in this case the two major cellular targets are β-tubulin and P-gp.
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U2 - 10.1021/acs.jnatprod.7b01047
DO - 10.1021/acs.jnatprod.7b01047
M3 - Article
C2 - 29517223
AN - SCOPUS:85044519278
SN - 0163-3864
VL - 81
SP - 600
EP - 606
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 3
ER -
