The clinically widely-used anticancer drug, cisplatin, binds strongly to DNA as a DNA-damaging agent. Herein, we investigated the interaction of cisplatin with a 15-mer single-stranded C,T-rich oligodeoxynucleotide, 5′-CCTT₄CTT₇G₈C₉T₁₀TCTCC-3′ (ODN15), using ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) in conjunction with tandem mass spectrometry (top-down MS). Top-down MS analysis with collision-induced dissociation (CID) fragmentation of the mono-platinated and di-platinated ODN15 provided abundant and informative Pt-containing or Pt-free a/[a − B], w and internal fragments, allowing the unambiguous identification of T₄, T₇, C₉, and T₁₀ as the platination sites on the cisplatin-ODN15 adducts. These results revealed that, in addition to the well-established guanine site, the unexpected thermodynamic binding of cisplatin to cytosine and thymine bases was also evident at the oligonucleotide level. Furthermore, the binding models of cisplatin with cytosine and thymine bases were built as the Pt coordinated to cytosine-N(3) and thymine-N(3) with displacement of the proton or tautomerization of thymine. These findings contribute to a better understanding of the mechanism of action of cisplatin and its preference for gene loci when the drug binds to cellular DNA, and also demonstrate the great potential and superiority of FT-ICR MS in studying the interactions of metallodrugs with large biomolecules.

Strophanthidin (SPTD), one of the cardiac glycosides, is refined from traditional Chinese medicines such as Semen Lepidii and Antiaris toxicaria, and was initially used for the treatment of heart failure disease in clinic. Recently, SPTD has been shown to be a potential anticancer agent, but the underlying mechanism of action is poorly understood. Herein, we explored the molecular mechanism by which SPTD exerts anticancer effects in A549 human lung adenocarcinoma cells by means of mass spectrometry-based quantitative proteomics in combination with bioinformatics analysis. We revealed that SPTD promoted the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2, or DR5) in A549 cells to activate caspase 3/6/8, in particular caspase 3. Consequently, the activated caspases elevated the expression level of apoptotic chromatin condensation inducer in the nucleus (ACIN1) and prelamin-A/C (LMNA), ultimately inducing apoptosis via cooperation with the SPTD-induced overexpressed barrier-to-autointegration factor 1 (Banf1). Moreover, the SPTD-induced DEPs interacted with each other to downregulate the p38 MAPK/ERK signaling, contributing to the SPTD inhibition of the growth of A549 cells. Additionally, the downregulation of collagen COL1A5 by SPTD was another anticancer benefit of SPTD through the modulation of the cell microenvironment.

Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the cytotoxicity of the genotoxic anticancer drug cisplatin, yet the underlying mechanism remains poorly understood. Herein, we revealed that TSA at a low concentration (1 μM) promoted the cisplatin-induced activation of caspase-3/6, which, in turn, increased the level of cleaved PARP1 and degraded lamin A&C, leading to more cisplatin-induced apoptosis and G2/M phase arrest of A549 cancer cells. Both ICP-MS and ToF-SIMS measurements demonstrated a significant increase in DNA-bound platinum in A549 cells in the presence of TSA, which was attributable to TSA-induced increase in the accessibility of genomic DNA to cisplatin attacking. The global quantitative proteomics results further showed that in the presence of TSA, cisplatin activated INF signaling to upregulate STAT1 and SAMHD1 to increase cisplatin sensitivity and downregulated ICAM1 and CD44 to reduce cell migration, synergistically promoting cisplatin cytotoxicity. Furthermore, in the presence of TSA, cisplatin downregulated TFAM and SLC3A2 to enhance cisplatin-induced ferroptosis, also contributing to the promotion of cisplatin cytotoxicity. Importantly, our posttranslational modification data indicated that acetylation at H4K8 played a dominant role in promoting cisplatin cytotoxicity. These findings provide novel insights into better understanding the principle of combining chemotherapy of genotoxic drugs and HDAC inhibitors for the treatment of cancers.

The ruthenium polypyridine complex [Ru(dppa)₂(pytp)] (PF₆)₂ (termed as ZQX-1), where dppa = 4,7-diphenyl-1,10-phenanthroline and pytp = 4′-pyrene-2,2′:6′,2′′-terpyridine, has been shown a high and selective cytotoxicity to hypoxic and cisplatin-resistant cancer cells either under irradiation with blue light or upon two-photon excitation. The IC₅₀ values of ZQX-1 towards A549 cancer cells and HEK293 health cells are 0.16 ± 0.09 µM and >100 µM under irradiation at 420 nm, respectively. However, the mechanism of action of ZQX-1 remains unclear. In this work, using the quantitative proteomics method we identified 84 differentially expressed proteins (DEPs) with |fold-change| ≥ 1.2 in A549 cancer cells exposed to ZQX-1 under irradiation at 420 nm. Bioinformatics analysis of the DEPs revealed that photoactivated ZQX-1 generated reactive oxygen species (ROS) to activate oxidative phosphorylation signaling to overproduce ATP; it also released ROS and pyrene derivative to damage DNA and arrest A549 cells at S-phase, which synergistically led to oncotic necrosis and apoptosis of A549 cells to deplete excess ATP, evidenced by the elevated level of PRAP1 and cleaved capase-3. Moreover, the DNA damage inhibited the expression of DNA repair-related proteins, such as RBX1 and GPS1, enhancing photocytotoxicity of ZQX-1, which was reflected in the inhibition of integrin signaling and disruption of ribosome assembly. Importantly, the photoactivated ZQX-1 was shown to activate hypoxia-inducible factor 1A (HIF1A) survival signaling, implying that combining use of ZQX-1 with HIF1A signaling inhibitors may further promote the photocytotoxicity of the prodrug.

CO₂ is a greenhouse gas and a nontoxic, easily available and renewable C₁ feedstock. H₂ is a clean and cheap reductant that can be obtained from renewable energy. Olefins are platform chemicals that can be produced from a variety of raw materials such as petroleum, coal and renewable biomass. The production of carboxylic acids by combining olefins, CO₂ and H₂ is a sustainable and very promising protocol. However, only a few advances in this topic have been achieved because novel catalysts need to be developed. In this work, we demonstrate that a simple iridium-based catalyst could efficiently promote the synthesis of C₂₊ carboxylic acids via the reaction of olefins with CO₂ and H₂. The reaction was effectively accelerated by a simple iridium-based catalytic system at 170 °C, which may be applied to various olefin substrates. The catalytic mechanism was studied through a series of control experiments. The findings contribute to advancing the sustainable production of valuable products by the reaction of renewable CO₂ and green H₂ with platform chemicals.

The oxygen-evolving center (OEC) in photosynthesis is a unique biological Mn₄CaO₅-cluster that splits water into electrons, protons, and dioxygen. It is a great challenge for chemists to develop a robust and precise mimic of the OEC in the laboratory. Herein, we report the formation of a rare-earth-element-containing Mn₄YO₄-cluster that represents an excellent and robust model of the OEC. The key synthetic precursor, the Mn₃YO₂-cluster, is reported for the first time, which possesses an identical mixed-valence Mn^III₂Mn^IV metal core and a hydrogen-bonding network coordination sphere. This precursor is very reactive and can convert into various compounds in solution. Importantly, it has been found that the presence of organic bases significantly influences the distribution of intermediates and promotes the formation of the Mn₄YO₄-cluster. Meanwhile, two Mn₄YO₄-clusters are described, which closely mimic the main metal-oxide core and peripheral ligands, as well as the oxidation states of the four Mn ions in the OEC, revealing that both the terminal ligands and a bridging carboxylate are variable. This new Mn₄YO₄-cluster displays a remarkable stability in the presence of water in acetonitrile solution. These findings shed new light on the synthesis of rare-earth-element-containing clusters and the rational design of robust artificial water-splitting catalysts, and provide chemical insights into the dynamic structural changes of both biological and artificial clusters.