Carboplatin as an alternative to Cisplatin in chemotherapies: New insights at single molecule level

Abstract

Here we report a new study performed at single molecule level on the interaction of the antineoplastic drug Carboplatin and the DNA molecule - the main target of the drug inside cells in cancer chemotherapies. By using optical tweezers, we measure how the mechanical properties of the DNA-Carboplatin complexes changes as a function of the drug concentration in the sample, for two different ionic strengths ([Na] = 150 mM and [Na] = 1 mM). From these measurements, the binding mechanism and the physicochemical (binding) parameters of the interaction were inferred and directly compared to those obtained for the precursor drug Cisplatin under equivalent conditions. As the main conclusion, we show that Carboplatin binds preferentially forming covalent monoadducts in contrast to Cisplatin, which is hydrolyzed easier and presents a higher efficiency in forming covalent diadducts along the double-helix. In addition, we explicitly show that Carboplatin is much less sensitive to ionic strength changes when compared to Cisplatin. These findings provide new insights on the interactions of platinum-based compounds with the DNA molecule, being important to improve the current treatments and in the development of new antineoplastic agents.

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

“… a The equivalent results for the situation without caffeine, obtained in previous works, − are also shown for comparison purposes. K is the equilibrium association binding constant and n is the Hill exponent, which measures the cooperativity of the binding reactions. …”

“…To express the bound site fraction r in the equation mentioned above as a function of the ligand concentration in solution, we choose a convenient binding isotherm able to capture the physical chemistry of the binding reaction. In order to rigorously compare the binding parameters determined here with those determined in previous works for the situation without caffeine in the sample, − we choose the Hill binding isotherm, which can be written as where C f is the free (not bound to DNA) drug concentration in the sample, K is the equilibrium association binding constant, and n is the Hill exponent, a parameter that quantifies the degree of cooperativity of binding reactions …”

“…The complete details of the fitting procedure performed with this approach can be found in a previous work . As will be evident in the next section when we present the results, the Hill exponent can be fixed to unity in all the fittings when caffeine is present in the sample because the alkaloid hindered any cooperativity present in the original binding reactions (without caffeine) of some of the tested platinum drugs. , …”

“…Platinum-based drugs constitute one of the classes of compounds most employed in current cancer chemotherapies. − Because of the success achieved in clinical trials using these drugs, over the past years, a number of groups have investigated the molecular mechanism of action of cisplatin and its derivatives, especially their interactions with the DNA moleculethe main target of these drugs inside living cells. − It is known that the platinum-based compounds can form a variety of different covalent adducts with the DNA bases. Such structures are recognized as the cause of their antitumor activity, resulting in an effective hindering of many intracellular DNA-related processes. , …”

Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer

“…Loosely classified as a platinum-containing alkylating agent, cisplatin undergoes hydrolysis in the cytoplasm and binds to the N7 reactive center on purines in order to crosslink DNA 17 . Due to its toxicity, derivatives of cisplatin exist, such as carboplatin which exhibit both reduced effect and toxicity compared to cisplatin 18 . Gemcitabine, while also a DNA replication inhibitor, is instead an antimetabolite which disables topoisomerase I 19 .…”