Mitochondrial Permeability Transition as Target of Anticancer Drugs

Title:Mitochondrial Permeability Transition as Target of Anticancer Drugs

Volume: 20 Issue: 2

Author(s): Lisa Dalla Via, Aida N. Garcia-Argaez, Mariano Martinez-Vazquez, Silvia Grancara, Pamela Martinis and Antonio Toninello

Affiliation:

Keywords: Mitochondria, Permeability transition, Antiproliferative effect, Natural compounds, Peniocerol.

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 Ca²⁺ 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.

Cite this article as:

Via Dalla Lisa, Garcia-Argaez N. Aida, Martinez-Vazquez Mariano, Grancara Silvia, Martinis Pamela and Toninello Antonio, Mitochondrial Permeability Transition as Target of Anticancer Drugs, Current Pharmaceutical Design 2014; 20 (2) . https://dx.doi.org/10.2174/13816128113199990033