5-diphenylacetamido-indirubin-3'-oxime as a novel mitochondria-targeting agent with anti-leukemic activities

Ju Han Song, Jung Eun Lee, Kyung Min Cho, Su Ho Park, Hyeoung Joon Kim, Yong Chul Kim, Tae Sung Kim

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Current treatment for leukemia largely depends on chemotherapy. Despite the progress in treatment efficacy of chemotherapy, a poor outcome consequent upon chemoresistance against conventional anti-cancer drugs still remains to be solved. In this study, we report 5-diphenylacetamido-indirubin-3'-oxime (LDD398) as a novel mitochondria-targeting anti-leukemic agent, which is a derivative of indirubin used in traditional medicine. Treatment with LDD398 resulted in caspase activation, cell death, and growth arrest at G2/M phases in leukemia cells. Interestingly, LDD398 quickly collapsed mitochondrial membrane potential (MMP) within 1h, accompanied by cytochrome c release into cytosol and severe depletion of cellular ATP. However, the LDD398-induced cellular events was significantly mitigated by blockage of mitochondrial permeability transition pore (MPTP) opening with chemical and genetic modifications, strongly supporting that LDD398 executes its anti-leukemic activity via an inappropriate opening of MPTP and a consequent depletion of ATP. The most meaningful finding was the prominent effectiveness of LDD398 on primary leukemia cells and also on malignant leukemia cells resistant to anticancer drugs. Our results demonstrate that, among a series of indirubin derivatives, LDD398 induces leukemia cell death via a different mode from indirubin or conventional chemotherapeutics, and can be employed as a potent anti-cancer agent in the treatment for newly diagnosed and relapsed leukemia.

Original languageEnglish
JournalMolecular Carcinogenesis
DOIs
Publication statusAccepted/In press - 2015

Fingerprint

Oximes
Mitochondria
Leukemia
Cell Death
Adenosine Triphosphate
Drug Therapy
Mitochondrial Membrane Potential
G2 Phase
Traditional Medicine
Caspases
Cytochromes c
Pharmaceutical Preparations
Cell Division
Cytosol
indirubin
Neoplasms
Therapeutics
Growth

Keywords

  • Chemotherapy
  • Drug-resistance
  • Indirubin derivative
  • Leukemia
  • Mitochondria

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

5-diphenylacetamido-indirubin-3'-oxime as a novel mitochondria-targeting agent with anti-leukemic activities. / Song, Ju Han; Lee, Jung Eun; Cho, Kyung Min; Park, Su Ho; Kim, Hyeoung Joon; Kim, Yong Chul; Kim, Tae Sung.

In: Molecular Carcinogenesis, 2015.

Research output: Contribution to journalArticle

Song, Ju Han ; Lee, Jung Eun ; Cho, Kyung Min ; Park, Su Ho ; Kim, Hyeoung Joon ; Kim, Yong Chul ; Kim, Tae Sung. / 5-diphenylacetamido-indirubin-3'-oxime as a novel mitochondria-targeting agent with anti-leukemic activities. In: Molecular Carcinogenesis. 2015.
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