Mitochondrial permeability transition as target of anticancer drugs

Curr Pharm Des. 2014;20(2):223-44. doi: 10.2174/13816128113199990033.

Abstract

Mitochondria are the cell powerhouses but also contain the mechanisms leading to cell death. Many signals converge on mitochondria to cause the permeabilization of mitochondrial membranes by the mitochondrial permeability transition (MPT) induction and the opening of transition pores (PTPs). These events cause loss of ionic homeostasis, matrix swelling, outer membrane rupture leading to pro-apoptotic factors release, and impairment of bioenergetics functions. The molecular mechanism underlying MPT induction is not completely elucidated however, a growing body of evidence supports the concept that pharmacological induction of PTPs in mitochondria of neoplastic cells is an effective and promising strategy for therapeutic approaches against cancer. The first part of this article presented as a review also evidences the main constituents of PTP and several compounds targeting them for inducing the phenomenon. The second part of the article regards the recent experimental development in the field, in particular, the effects of peniocerol (PEN), a sterol isolated from the root of Myrtillocactus geometrizans, at cellular and mitochondrial level. PEN exhibits a cytotoxic activity on some human tumor cell lines, whose mechanism is attributable to the oxidation of critical thiols located on adenine nucleotide translocase, the protein mainly involved in PTP. This event in the presence of Ca(2+) induces the MPT with the release of the pro-apoptotic factors cytochrome c and apoptosis inducing factor. These observations evidence that PEN may trigger both the caspase-dependent and caspaseindependent apoptotic pathways. This characteristic renders PEN a very interesting compound that could be developed to obtain more effective antiproliferative agents targeting mitochondria for anticancer therapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Inducing Factor / metabolism
  • Cactaceae / chemistry
  • Caspases / metabolism
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Permeability Transition Pore
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Sterols / isolation & purification
  • Sterols / pharmacology*

Substances

  • Antineoplastic Agents
  • Apoptosis Inducing Factor
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Sterols
  • peniocerol
  • Caspases