The disulfide compound α-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondria

Cancer Lett. 2016 Feb 1;371(1):12-9. doi: 10.1016/j.canlet.2015.11.019. Epub 2015 Nov 18.


The endogenous disulfide α-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties.

Keywords: Anticancer drugs; Apoptosis; Cancer therapy; Cell death; Mitochondria; α-lipoic acid.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Caprylates / chemistry
  • Caprylates / pharmacokinetics
  • Caprylates / therapeutic use*
  • Drug Discovery
  • Energy Metabolism / drug effects
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Sulfides / chemistry
  • Sulfides / pharmacokinetics
  • Sulfides / therapeutic use*
  • Thioctic Acid / analogs & derivatives
  • Thioctic Acid / chemistry
  • Thioctic Acid / pharmacokinetics
  • Thioctic Acid / therapeutic use*


  • Antineoplastic Agents
  • Caprylates
  • Sulfides
  • Thioctic Acid
  • devimistat