Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1.
To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI-National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations-indicative of MDR1-mediated resistance-were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.
Huang
Y
Y
Department of Pharmacology, Comprehensive Cancer Center, College of Medicine and Public Health, The Ohio State University, Columbus, OH 4321-1239, USA.
Blower
P E
PE
Yang
C
C
Barbacioru
C
C
Dai
Z
Z
Zhang
Y
Y
Xiao
J J
JJ
Chan
K K
KK
Sadée
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D015342:DNA Probes; D016208:Databases, Factual; D015536:Down-Regulation / Q000187:drug effects; D004611:Ellipticines / Q000378:metabolism* / Q000494:pharmacology*; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D008490:Medical Informatics; D017239:Paclitaxel / Q000633:toxicity; D025341:Principal Component Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D015342:DNA Probes; D004611:Ellipticines; D005456:Fluorescent Dyes; D034741:RNA, Small Interfering; D017239:Paclitaxel