Targeting Cancer Cell Mitochondria as a Therapeutic Approach

Abstract

Mitochondria are double membrane-enveloped organelles that play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. They function as main generators of ATP, metabolites for the construction of macromolecules and reactive oxygen species. In many cancer cells, mitochondria seem dysfunctional, manifested by a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase in reactive oxygen species generation. These metabolic changes are often associated with upregulation of NAD(P)H oxidase. Importantly, the metabolic reprogramming in a cancer cell is mechanistically linked to oncogenic signals. Targeting mitochondria as a cancer therapeutic strategy has attracted much attention in the recent years and multiple review articles in this area have been published. This article attempts to provide an update on recent progress in identification of mitochondria-associated molecules as potential anticancer targets and the respective targeting compounds.

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].…”

“…A major milestone towards organelle-specific drug delivery was reached by the discovery of delocalized lipophilic cations (DLCs) [11]. 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].…”

Chrysin induces cell apoptosis via activation of the p53/Bcl-2/caspase-9 pathway in hepatocellular carcinoma cells

“…Drug-induced cell apoptosis is due to mitochondrial dysfunction and apoptotic signaling pathway activation (13). p53, B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter (Bad), Bcl-2-associated X (Bax), Bcl-2 homologous antagonist/killer (Bak), caspase-9 and caspase-3 are associated with apoptosis-induced mitochondrial damage (14); therefore the expression levels of these proteins were investigated.…”

A Molecular Hybrid for Mitochondria‐Targeted NO Photodelivery

“…This intermediate was dissolved in dry CH 2 Cl 2 (15 mL), diethylamine hydrochloride (124 mg, 1.1 mmol) and an excess of triethylamine (0.5 mL) were added and the resulting solution was stirred for 18 h. The reaction mixture was washed with water (3 15 mL), saturated sodium bicarbonate solution (3 15 mL) and 1 m HCl (3 15 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography using CH 2 HNMR and 13 CNMR spectra were recorded on aB ruker Avance 300 instrument at 300 and 75 MHz, respectively,a nd calibrated using SiMe 4 as an internal reference. UV/Vis spectra absorption and fluorescence emission spectra were recorded on aJascoV-560 spectrophotometer and aS pex Fluorolog-2 (model F-111)s pectrofluorimeter,r espectively,i na ir-equilibrated solutions, using quartz cells with ap ath length of 1cm.…”

“…[1][2][3] Interestingly, cancer cells show peculiar mitochondrial dysfunctions that can be harnessed for selectivet oxicity,w ith respect to normaltransformed cells. [4,5] Nitric oxide (NO), au biquitous messenger which plays important roles in many physiological and pathological processes, [6,7] exerts profound effects on mitochondria.…”