The Mechanism of Dynamic Interaction between Doxorubicin and Calf Thymus DNA at the Single-Molecule Level Based on Confocal Raman Spectroscopy

Abstract

It is of great fundamental significance and practical application to understand the binding sites and dynamic process of the interaction between doxorubicin (DOX) and DNA molecules. Based on the Confocal Raman spectroscopy, the interaction between DOX and calf thymus DNA has been systemically investigated, and some meaningful findings have been found. DOX molecules can not only interact with all four bases of DNA molecules, i.e., adenine, thymine, cytosine, guanine, and phosphate, but also affect the DNA conformation. Meanwhile, the binding site of DOX and its derivatives such as daunorubicin and epirubicin is certain. Furthermore, the interaction between DOX and DNA molecules is a dynamic process since the intensities of each characteristic peaks of the base, e.g., adenine, cytosine, and phosphate, are all regularly changed with the interaction time. Finally, a dynamic mechanism model of the interaction between DOX and DNA molecules is proposed; that is, there are two kinds of interaction between DOX and DNA molecules: DOX-DNA acts to form a complex, and DOX-DOX acts to form a multimer. The two effects are competitive, as the former compresses DNA molecules, and the latter decompresses these DNA molecules. This work is helpful for accurately understanding and developing new drugs and pathways to improve and treat DOX-induced cytotoxicity and cardiotoxicity.

UV-Resonance Raman Spectra of Systems in Complex Environments: A Multiscale Modeling Applied to Doxorubicin Intercalated into DNA

“…Spectroscopy, and RR in particular, has been crucial for studying DOX in various environments, including DNA. Table S2 in the SI reports important contributions with a variety of techniques. − Indeed, many authors have pointed out spectroscopic consequences upon intercalation in the cases of absorption, fluorescence, Raman, and remarkably RR spectra. , …”

“…Table S2 in the SI reports important contributions with a variety of techniques. 48 − 62 Indeed, many authors have pointed out spectroscopic consequences upon intercalation in the cases of absorption, fluorescence, Raman, and remarkably RR spectra. 51 , 56 …”

Interaction of Doxorubicin Embedded into Phospholipid Nanoparticles and Targeted Peptide-Modified Phospholipid Nanoparticles with DNA

“…DOX, a widely used cancer drug, is applied to treat breast, lung, stomach, ovarian, thyroid cancer, soft tissue and bone sarcomas, gastric, non-Hodgkin’s and Hodgkin’s lymphoma, sarcoma, pediatric cancers, leukemia, and multiple myeloma [ 1 ]. Mechanisms of DOX toxicity have been described previously [ 2 , 3 , 4 , 5 , 6 ]. The main mechanism of pharmacological activity of doxorubicin involves the ability of the drug to intercalate into DNA base pairs, and/or covalently bind to proteins involved in DNA replication and transcription, leading to inhibition of both DNA and RNA synthesis.…”

“…DOX inhibits the enzyme topoisomerase II, which is explained by DOX intercalation into DNA, causing DNA damage and induction of apoptosis [ 2 , 3 ]. DOX oxidation to semiquinone, an unstable metabolite, which is converted back to DOX in a process, releases reactive oxygen species that cause DNA damage and lipid peroxidation [ 4 , 5 , 6 ]. Because of this process, reactive oxygen species are redistributed in the cell, which can lead to more intensive lipid peroxidation and membrane damage, DNA damage, oxidative stress, and triggering of apoptotic pathways of cell death [ 2 , 3 , 4 , 5 , 6 ].…”

Interaction between anticancer drug bendamustine and calf thymus DNA with spectroscopy at the single-molecule level

“…(a) Raman spectrum of ctDNA without BENDA; (b) Raman spectrum of ctDNA with BENDA present, c(ctDNA) = 9.5 × 10 -2 mol /L, c(BENDA) = 1.0 × 10 -2 mol /L.It is clear from the Raman spectra of ctDNA solutions (black spectral lines) that the main Raman peaks of ctDNA solutions are 673, 730, 750, 784, 802, 831, 1012, 1064, 1099, 1237, 1251, 1261, 1307, 1335, 1376, 1486 and 1576 cm -1 , respectively. The peak attribution of these characteristic peaks was determined according to the literature[23][24][25][26]. Among them, the characteristic peaks at 673 and 750 cm -1 are attributed to thymine (T) vibrations, while 730 cm -1 is attributed to adenine (A) vibrations.…”