Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy

Abstract

Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level.This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(II) and Pd(II) dinuclear chelates with spermine (Pt 2 Spm and Pd 2 Spm), using cisplatin (cis-Pt(NH 3 ) 2 Cl 2 ) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 mM) at 48 h exposure.Multivariate data analysis was applied (unsupervised PCA), unveiling drug-and concentration-dependent effects: apart from discrimination between control and drugtreated cells, a clear separation was obtained for the different agents studiedmononuclear vs. polynuclear, and Pt(II) vs. Pd(II). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(II) agent having a more significant impact on proteins while its Pt(II) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents.

Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent

“…Indeed, this polynuclear Pd(II) complex is therefore shown to be a very promising antitumour agent, corroborating previous studies by the authors published by our group in other cells lines such as MCF-7 [12] reporting a high impact on proteins and DNA backbone [41] as compared to its Pt(II) homologue and cisplatin, as well as a significant effect on cell morphology particularly targetting the cytoskeleton (mostly the microtubules, [12]), that may explain, at least in part, the anti-angiogenic effect presently observed associated to the inhibition of tubular-like structure formation [37]: these compounds have been shown to display a higher cytotoxicity towards breast cancer (namely TNBC [12]), due to a more severe DNA damage via long-range interstrand drug–DNA adducts not available to conventional drugs [42]. …”

Shedding light into the health‐beneficial properties of Corema album—A vibrational spectroscopy study

“…[16,17] Raman microspectroscopy, in particular, is a cutting-edge technique that enables an accurate and non-invasive profiling of biological samples of several types (e.g., plants, human cells, or tissues), virtually without interference from water, yielding unique chemical fingerprints. [18][19][20][21] Actually, the high sensitivity and subcellular spatial resolution of microRaman allows us to detect the smallest chemical variations and conformational rearrangements even in heterogeneous biological models such as leaves, fruits, or seeds. In turn, FTIR in attenuated total reflectance mode (FTIR-ATR) is particularly suitable for routine analysis because it is easily accessible, inexpensive, fast, and requires no sample preparation.…”

Anticancer Drug Impact on DNA – A Study by Neutron Spectrocopy, Synchrotron-based FTIR and EXAFS

“…The dinuclear complexes Pt 2 Spm and Pd 2 Spm have been studied by the authors in the last few years and have been shown to act as promising anticancer agents towards human metastatic breast cancer (Batista de Carvalho et al, 2016a, Batista de Carvalho et al, 2016b, Fiuza et al, 2011, Marques et al, 2002, Silva et al, 2013 and osteosarcoma (Lamego et al, 2017). A multidisciplinary study was presently carried out to attain complementary structural and dynamical information on their interplay with DNA (their main pharmacological target), using QENS measurements, SR-FTIR and SR-EXAFS/XANES.…”

“…These results, including complementary data regarding the lower frequency spectral range not previously probed, are in good accordance with the information formerly obtained (by EXAFS, FTIR, Raman and INS) for DNA´s purine bases upon cisplatin binding. (Batista de Carvalho et al, 2016b In addition, valuable information was gathered on a different interplay with the nucleic acid regarding the dinuclear agents Pt 2 Spm and Pd 2 Spm as compared to the mononuclear (clinically used) drug cisplatin.…”

“…(Fiuza, Holy et al, 2011) A number of studies have been conducted in the last few years on these Pt-and Pd-based complexes, reporting conformational profiles (Batista de Carvalho, Parker et al, 2018, Fiuza, Amado et al, 2015, Marques, Valero et al, 2013 and pharmacokinetic/pharmacodynamic behaviour, (Corduneanu, Chiorcea-Paquim et al, 2010, Marques, Gianolio et al, 2015 and the effect on different human cancers(Batista de Carvalho, Medeiros et al, 2016a, Fiuza, Amado et al, 2006, Fiuza et al, 2011, Marques, Girao et al, 2002, Silva, Andersson et al, 2013, Silva, Fiuza et al, 2014, Soares, Fiuza et al, 2007, Tassoni, Bagni et al, 2010, Teixeira, Seabra et al, 2004, Tummala, Diegelman et al, 2010 including their impact on cellular biochemical profile. (Batista de Carvalho, Pilling et al, 2016b, Lamego, Marques et al, 2017, Marques, Batista de Carvalho et al, 2017 Unconventional pathways of cytotoxicity were disclosed, which are recognized to lead to an improved therapeutic efficiency coupled to a lower toxicity. In addition, the data gathered so far suggests distinct mechanisms of action for the Pt(II) versus the Pd(II) agents, as well as for the dinuclear polyamine chelates relative to the mononuclear lead drug cisplatin.…”