Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase

Shigeyuki Magi, Tetsuo Shitara, Yasushi Takemoto, Masato Sawada, Mitsuhiro Kitagawa, Etsu Tashiro, Yoshikazu Takahashi, Masaya Imoto

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 IC 50 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.

Original languageEnglish
Pages (from-to)165-170
Number of pages6
JournalJournal of Antibiotics
Volume66
Issue number3
DOIs
Publication statusPublished - 2013 Mar

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Aclarubicin
Cell Migration Inhibition
Transferases
Neoplasms
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor
Geranylgeranyl-Diphosphate Geranylgeranyltransferase
Cell Movement
Prenylation
Cultured Cells
aclacinomycins
N-allyl-aclacinomycin A
N-benzyl-aclacinomycin A
Membranes

Keywords

  • aclacinomycin A
  • cancer cell migration
  • farnesyl transferase

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase. / Magi, Shigeyuki; Shitara, Tetsuo; Takemoto, Yasushi; Sawada, Masato; Kitagawa, Mitsuhiro; Tashiro, Etsu; Takahashi, Yoshikazu; Imoto, Masaya.

In: Journal of Antibiotics, Vol. 66, No. 3, 03.2013, p. 165-170.

Research output: Contribution to journalArticle

Magi, Shigeyuki ; Shitara, Tetsuo ; Takemoto, Yasushi ; Sawada, Masato ; Kitagawa, Mitsuhiro ; Tashiro, Etsu ; Takahashi, Yoshikazu ; Imoto, Masaya. / Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase. In: Journal of Antibiotics. 2013 ; Vol. 66, No. 3. pp. 165-170.
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