Caffeine Enhances the Toxicity of Platinum-Based Drugs at the Molecular Level Even Outside of the Intracellular Environment: A Single-Molecule Force Spectroscopy Study

It is well reported in the literature that caffeine, the most consumed alkaloid around the world, enhances the anticancer effects of the drug cisplatin by inhibiting DNA repair by the cellular machinery. Here, we perform single-molecule force spectroscopy assays with optical tweezers to show that caffeine enhances the toxicity not only of cisplatin but also of various different platinum-based drugs already at the molecular level, using samples containing only double-stranded (ds)DNA, platinum drugs, and the alkaloid in a simple phosphate buffer, that is, completely out of the complex environment found inside real living cells. In fact, our results show that caffeine acts as an allosteric catalyst which increases the effective equilibrium binding constant between DNA and the platinum drugs, also interfering in the cooperativity of the binding reactions. To the best of our knowledge, this is the first time that such a property of caffeine was demonstrated and characterized from a pure physicochemical perspective, outside the cellular environment. Thus, the present work provides new insights into the use of this alkaloid for current chemotherapeutic applications.