Chemotherapeutic Targets in Osteosarcoma: Insights from Synchrotron-MicroFTIR and Quasi-Elastic Neutron Scattering

Abstract

This study aimed at the development of improved drugs against human osteosarcoma, which is the most common primary bone tumor in children and teenagers with a low prognosis available treatment. New insights into the impact of an unconventional Pd(II) anticancer agent on human osteosarcoma cells were obtained by synchrotron-based infrared microspectroscopy (SR-microFTIR) and quasi-elastic neutron scattering (QENS) experiments from its effect on the cellular metabolism to its influence on intracellular water which can be regarded as a potential secondary pharmacological target. Specific infrared biomarkers of drug

Cytotoxicity of Platinum and Palladium Chelates against Osteosarcoma

“…The IC 50 values increase in the following order: cDDP < OXA < Pt 2 Spm. It has been verified by the authors, in previous studies using other methodologies (namely vibrational spectroscopy and neutron-based techniques for evaluation drug-elicited changes in the metabolic profile and cellular dynamics [20,[43][44][45] ), that mononuclear drugs (namely cDDP and OXA) and dinuclear agents Pt 2 Spm/Pd 2 Spm have distinct modes of action (particularly regarding their interaction with DNA), which impact differently on cellular function. Thus, it is expected that the corresponding IC 50 are indeed different for both types of compounds.…”

A New Look into the Mode of Action of Metal-Based Anticancer Drugs

“…Apart from the conventional interaction of metal-based agents with DNA through covalent binding (leading to conformational rearrangements), these types of drugs have been previously shown to cause a significant reorganisation of the water molecules surrounding the biomolecule, prompting an increased mobility within its hydration layer [12,15,16,19]. Upon these drug-elicited perturbations, DNA is rendered less-functional or fully nonfunctional, which leads to cell growth inhibition and cell death.…”

“…As suggested in previous studies by the authors [12,15,16,19], apart from the conventional targets of these type of metal-based agents (DNA and specific proteins), there may be other receptors that are relevant for chemotherapeutic activity, namely water molecules-both within the cytoplasm and the hydration layers of biomolecules. Intracellular water (cytoplasmic), which accounts for 70 to 80% of the whole cell mass, has a particular structural and dynamical behaviour namely its ability to form highly organised H-bond networks.…”

“…Cytotoxicity arises from the selective covalent binding of the metal ions to DNA purine bases at more than one site within the double helix, yielding long-range interstrand adducts. These agents have been synthesised and extensively investigated by the team, to provide a comprehensive set of data on (i) cytotoxicity towards several human cancer cells [6][7][8][9][10], (ii) interactions with DNA and glutathione-mediated resistance pathways [11,12] and (iii) impact on cellular metabolism and intracellular water [12][13][14][15][16]. Vibrational spectroscopy techniques were applied (including inelastic neutron scattering and synchrotron radiation-Fourier transform infrared (FTIR)) coupled to theoretical simulations [4,17,18], as well as synchrotron-based Extended X-ray Absorption Fine Structure (EXAFS) [11].…”

“…Translational modes of water are changed near the biopolymers and appear in a different energy transfer range to the vibrations from the biomolecule itself, thus rendering INS a very useful tool to probe water. QENS, in turn, is a method of choice for directly accessing different spatially resolved dynamical processes of key biological components-from fast localised modes to slower global translations-and the way they are changed by the presence of a drug, [12,15,16,19,26,[35][36][37][38][39][40][41][42][43]. While QENS is a direct probe of water's dynamical behaviour, INS and the optical vibrational techniques Raman and FTIR indirectly monitor water properties which affect the corresponding vibrational profile while detecting conformational rearrangements of the biomolecule.…”