From delocalized lipophilic cations to hypoxia: Blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors

Abstract

An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracyclines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-D-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

“…Notably, following their pretreatment with DLC-carboranes, only normal cells were seen to recapitulate their full proliferation potential in media that were free from these compounds; this effect was verified through dilution assays. The selective effect of the functionized carboranes appears to be linked to their DLC moiety, which elicits a cytotoxic response with a therapeutic potential through mitochondrial targets [11,18], since: a) triphenylphosphonium ions (TPPs), have been exploited as small molecule directing groups to achieve mitochondrial delivery [17]; b) rhodamine functionalities have been utilized in mitochondria-specific dyes [11,15,20]; and, c) dequalinium (DQA) has been evaluated in a therapeutic approach for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), acute promyelocytic leukemia (APL) and hepatocellular carcinoma (HCC) [32,33]. [42,43].…”

“…These molecular structures are guided selectively towards tumors by the higher mitochondrial transmembrane potential (~60 mV difference) that is consequent to the correspondingly higher metabolic activity of cancer cells relative to that of normal cells [12][13][14][15][16]. The resonance-stabilized delocalization of the positive charge of DLCs, coupled with their inherent lipophilicity, leads to a decrease in the cost associated with the free energy change that accompanies the diffusion of DLCs through cell membranes, and provides the 5 driving force for their observed highly selective accumulation (>100 fold) in the mitochondrial matrix of cancer cells [13,17,18] and the associated high (>5 fold) difference between their cytoplasmic and extracellular concentrations [11]. Towards the development of highly selective target-specific anticancer agents that are applicable to boron neutron capture therapy (BNCT) of cancer, this study builds on preliminary evaluations that indicated the selective accumulation of boronated DLC compounds in cancer cells [19,20].…”

Methods for Detection of Mitochondrial and Cellular Reactive Oxygen Species

“…Recently, one cyclic nitrone, 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO), has been modified by addition of a triphenylphosphonium group, promoting its selective uptake by mitochondria (27). Unfortunately, the triphenylphosphonium conjugate of DEPMPO (mito-DEPM-PO) must also be used at high concentrations (50 mM), which may cause inhibition of mitochondrial ATP synthesis due to the accumulation of large amounts of the lipophilic cation in the mitochondrial matrix and alteration of the mitochondrial membrane potential (36). The use of this mito-DEPMPO spin trap is therefore likely limited by its slow rate constant for reaction with O 2 -(33), potential toxicity (34), and nonspecific effects (1), and its use in biological systems is therefore unlikely.…”

Cytochrome c modulates the mitochondrial signaling pathway and polymorphonuclear neutrophil apoptosis in bile duct-ligated rats

“…ΔΨm, which prevents apoptosis proteins (Cytc and so on) from being released from the mitochondria into the cytoplasm or nucleus, was detected using Rho-123 staining and FACS, and expressed as the MFI (22,23). When the Rho-123 MFI value is lower, the ΔΨm level is higher (26).…”