Repurposing of MitoTam: Novel Anti-Cancer Drug Candidate Exhibits Potent Activity against Major Protozoan and Fungal Pathogens

Abstract

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process.

Chelation of Mitochondrial Iron as an Antiparasitic Strategy

“…We have previously demonstrated that mitochondrially targeted tamoxifen directly disrupts the integrity of the IMM in T. brucei 427. 8 Using threonine dehydrogenase activity as a marker for the membrane permeability of isolated mitochondria, we observed a similar effect of mitoDFO (Figure 2D). Treatment with 63 μM mitoDFO increased inner membrane permeability by 50%, a milder effect than that of MitoTam, which should nevertheless be considered as one of the possible mechanisms of action of the compound.…”

“…1 Furthermore, we have observed the direct effect of mitoDFO on the integrity of the IMM at micromolar concentrations, analogously to that of mitochondrially targeted tamoxifen. 8 One of the relevant indicators of mitochondrial interference is the increased presence of free radicals, which we observed in T. brucei 427 upon exposure to mitoDFO. ROS levels can become dysregulated as a result of external stimuli, such as mitochondrial damage, or by inhibition of ROS-scavenging enzymes, such as superoxide dismutases, some of which are known to be irondependent in trypanosomatids.…”

“…7 Subsequently, MitoTam has been found to be effective against several protozoan parasites, both in vitro and in vivo. 8 Various derivatives of phosphonium salts have previously been studied as potential therapeutics against different parasitic organisms such as Leishmania and Trypanosoma, with the common finding that this class of compounds, as expected, affects mitochondrial energy metabolism, resulting in a drop in ATP levels combined with depolarization of mitochondrial membrane potential and possibly mitochondrial disintegration. 8−10 In addition, F O F 1 ATPase was speculated to be a possible target of this class of compounds.…”

“…This TPP-tagged Tamoxifen is acting via an altered mode of action and has been shown to be more selective than its untagged counterpart . Subsequently, MitoTam has been found to be effective against several protozoan parasites, both in vitro and in vivo …”

“…Various derivatives of phosphonium salts have previously been studied as potential therapeutics against different parasitic organisms such as Leishmania and Trypanosoma, with the common finding that this class of compounds, as expected, affects mitochondrial energy metabolism, resulting in a drop in ATP levels combined with depolarization of mitochondrial membrane potential and possibly mitochondrial disintegration. − In addition, F O F 1 ATPase was speculated to be a possible target of this class of compounds . To their advantage, it has been found that phosphonium salts do not rely on known drug transporters in Trypanosoma; therefore, their use as therapeutics could circumvent one common cause of drug-resistant phenotypes …”