Abstract
Targeting small molecules to appropriate subcellular compartments is a way to increase their selectivity and effectiveness while minimizing side effects. This can be accomplished either by stably incorporating specific “homing” properties into the structure of the active principle, or by attaching to it a targeting moiety via a labile linker, i.e., by producing a “targeting pro-drug.” Mitochondria are a recognized therapeutic target in oncology, and blocking the population of the potassium channel Kv1.3 residing in the inner mitochondrial membrane (mtKv1.3) has been shown to cause apoptosis of cancerous cells expressing it. These concepts have led us to devise novel, mitochondria-targeted, membrane-permeant drug candidates containing the furocoumarin (psoralenic) ring system and the triphenylphosphonium (TPP) lipophilic cation. The strategy has proven effective in various cancer models, including pancreatic ductal adenocarcinoma, melanoma, and glioblastoma, stimulating us to devise further novel molecules to extend and diversify the range of available drugs of this type. New compounds were synthesized and tested in vitro; one of them—a prodrug in which the coumarinic moiety and the TPP group are linked by a bridge comprising a labile carbonate bond system—proved quite effective in in vitro cytotoxicity assays. Selective death induction is attributed to inhibition of mtKv1.3. This results in oxidative stress, which is fatal for the already-stressed malignant cells. This compound may thus be a candidate drug for the mtKv1.3-targeting therapeutic approach.
Highlights
In therapeutic oncology, the ultimate goal is to cause the death of all cancerous and cancer stem cells while inflicting negligible damage to healthy cells and organs
We have extended the search for anti-tumoral agents combining the Kv1.3-inhibiting furocoumarin structure and the mitochondriotropic TPP group
One of the concepts we tested was to minimize the changes to the structure of the “parent” drug, Psora-4, while still turning it into a mitochondria-targeted drug
Summary
The ultimate goal is to cause the death of all cancerous and cancer stem cells while inflicting negligible damage to healthy cells and organs. One is to selectively hit only the unwanted cells with an effective death-inducing treatment. Examples of this approach include focused radiation therapy, the many attempts at delivering drugs selectively to tumoral cells, and immunotherapy. Another is aiming a drug at a molecular target which is expressed by cancer cells and/or whose function is more cogently needed by cancer cells than by healthy ones, including malfunctioning oncogenes. A third one may be to exploit an intrinsic characteristic of cancer cells, such as increased aerobic glycolysis (the Warburg effect) or their rapid growth and the associated redox stress
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