Shikonin Derivative DMAKO-05 Inhibits Akt Signal Activation and Melanoma Proliferation

Chem Biol Drug Des. 2016 Jun;87(6):895-904. doi: 10.1111/cbdd.12722. Epub 2016 Feb 18.

Abstract

DMAKO-05((S)-1-((5E,8E)-5,8-bis(hydroxyimino)-1,4-dimethoxy-5,8-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-methylbutanoate) is a novel oxime derivative of shikonin, the major component extracted from Chinese herb Lithospermun erythrorhizon. Here, we report that DMAKO-05 had an antitumor activity against mouse melanoma cell line B16F0. Our studies indicated that DMAKO-05 not only inhibited B16F0 proliferation and migration but also led to cell cycle arrest at G1 phase and cell apoptosis, in which DMAKO-05 triggered mitochondrial-mediated apoptosis signal including caspase-9/3 and PARP. In response to DMAKO-05 treatment, the Akt-mediated survival signals were remarkably attenuated in B16F0 cells. Collectively, DMAKO-05 has a strong cytotoxicity in B16F0 cells via inhibiting Akt activation, inducing G1 arrest, and promoting B16F0 cell apoptosis. DMAKO-05 might serve as a potential candidate lead compound for melanoma.

Keywords: DMAKO-05; apoptosis; cell cycle arrest; cytotoxicity; melanoma cell B16F0; shikonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic* / chemical synthesis
  • Antineoplastic Agents, Phytogenic* / chemistry
  • Antineoplastic Agents, Phytogenic* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Screening Assays, Antitumor
  • Melanoma* / drug therapy
  • Melanoma* / metabolism
  • Naphthoquinones* / chemical synthesis
  • Naphthoquinones* / chemistry
  • Naphthoquinones* / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents, Phytogenic
  • Naphthoquinones
  • shikonin
  • Proto-Oncogene Proteins c-akt