Enhancing chemosensitivity in ABCB1- and ABCG2-overexpressing cells and cancer stem-like cells by an Aurora kinase inhibitor CCT129202.
Imidazopyridine CCT129202 is an inhibitor of Aurora kinase activity and displays a favorable antineoplastic effect in preclinical studies. Here, we investigated the enhanced effect of CCT129202 on the cytotoxicity of chemotherapeutic drugs in multidrug resistant (MDR) cells with overexpression of ATP-binding cassette (ABC) transporters and cancer stem-like cells. CCT129202 of more than 90% cell survival concentration significantly enhanced the cytotoxicity of substrate drugs and increased the intracellular accumulations of doxorubicin and rhodamine 123 in ABCB1 and ABCG2 overexpressing cells, while no effect was found on parental sensitive cells. Interestingly, CCT129202 also potentiated the sensitivity of cancer stem-like cells to doxorubicin. Importantly, CCT129202 increased the inhibitory effect of vincristine and paclitaxel on ABCB1 overexpressing KBv200 cell xenografts in nude mice and human esophageal cancer tissue overexpressing ABCB1 ex vivo, respectively. Furthermore, the ATPase activity of ABCB1 was inhibited by CCT129202. Homology modeling predicted the binding conformation of CCT129202 within the large hydrophobic cavity of ABCB1. On the other hand, CCT129202 neither apparently altered the expression levels of ABCB1 and ABCG2 nor inhibited the activity of Aurora kinases in MDR cells under the concentration of reversal MDR. In conclusion, CCT129202 significantly reversed ABCB1- and ABCG2-mediated MDR in vitro, in vivo and ex vivo by inhibiting the function of their transporters and enhanced the eradication of cancer stem-like cells by chemotherapeutic agents. CCT129202 may be a candidate as MDR reversal agent for antineoplastic combination therapy and merits further clinical investigation.
Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
Chao
C
Cheng
Zhen-guo
ZG
Liu
Hui
H
Zhang
Jing-dun
JD
Xie
Xing-gui
XG
Chen
Xiao-qin
XQ
Zhao
Fang
F
Wang
Yong-ju
YJ
Liang
Li-kun
LK
Chen
Satyakam
S
Singh
Jun-jiang
JJ
Chen
Tanaji T
TT
Talele
Zhe-sheng
ZS
Chen
Fo-tian
FT
Zhong
Li-wu
LW
Fu
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D045744:Cell Line, Tumor; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C527332:CCT129202; D007093:Imidazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D064127:Aurora Kinases