A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells.
The purpose of this study was to evaluate the enhancement value of chloroquine analogs when used in combination with Akt inhibitors on the MDA-MB468, MDA-MB231 and MCF7 human breast cancer cell lines. The result showed that the combination of certain chloroquine analogs and Akt inhibitors are highly effective. In particular, the chloroquine analog N'-(7-fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine (compound 5) was highly effective in sensitizing cancer cell killing when combined with either Akt inhibitor 8 (1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one) or 9 ([4-(2-chloro-4a,10a-dihydro-phenoxazin-10-yl)-butyl]-diethyl-amine hydrochloride). Importantly, the enhancement of chloroquine analogs 5 on cell killing by Akt inhibitors 8 and 9 was cancer-specific. Thus, this combinational approach is highly promising in controlling tumors with a minimum side effect. Structural analysis of effective and ineffective chloroquine analogs suggests that the 4-aminoquinoline scaffold and lateral side chain of dimethylamino functionality play an important role for the enhancement of cell killing by Akt inhibitors.
Hu
Changkun
C
Tumour Biology, Northeastern Ontario Regional Cancer Program at the Sudbury Regional Hospital, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada.
Raja Solomon
V
V
Cano
Pablo
P
Lee
Hoyun
H
D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
D000634:Aminoquinolines; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C001920:4-aminoquinoline