Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase.
In the course of screening for an inhibitor of farnesyl transferase (FTase), we identified two compounds, N-benzyl-aclacinomycin A (ACM) and N-allyl-ACM, which are new derivatives of ACM. N-benzyl-ACM and N-allyl-ACM inhibited FTase activity with IC50 values of 0.86 and 2.93 μM, respectively. Not only ACM but also C-10 epimers of each ACM derivative failed to inhibit FTase. The inhibition of FTase by N-benzyl-ACM and N-allyl-ACM seems to be specific, because these two compounds did not inhibit geranylgeranyltransferase or geranylgeranyl pyrophosphate (GGPP) synthase up to 100 μM. In cultured A431 cells, N-benzyl-ACM and N-allyl-ACM also blocked both the membrane localization of H-Ras and activation of the H-Ras-dependent PI3K/Akt pathway. In addition, they inhibited epidermal growth factor (EGF)-induced migration of A431 cells. Thus, N-benzyl-ACM and N-allyl-ACM inhibited EGF-induced migration of A431 cells by inhibiting the farnesylation of H-Ras and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.
Faculty of Science and Technology, Department of Biosciences and Informatics, Keio University, Yokohama, Japan.
Shigeyuki
S
Magi
Tetsuo
T
Shitara
Yasushi
Y
Takemoto
Masato
M
Sawada
Mitsuhiro
M
Kitagawa
Etsu
E
Tashiro
Yoshikazu
Y
Takahashi
Masaya
M
Imoto
D015250:Aclarubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019883:Alkyl and Aryl Transferases / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D011905:Genes, ras / Q000187:drug effects; D051232:Geranylgeranyl-Diphosphate Geranylgeranyltransferase / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C581056:N-allyl-aclacinomycin A; C581057:N-benzyl-aclacinomycin A; D004815:Epidermal Growth Factor; D015250:Aclarubicin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D051232:Geranylgeranyl-Diphosphate Geranylgeranyltransferase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt