Dataset Information

Study on the mechanism of action of the Pt(IV) complex with lonidamine ligands by ultrafast chemical proteomics

ABSTRACT: Platinum (II) complexes such as cisplatin among the few others are well-known and approved for clinical use as anticancer metal-based drugs. In spite of their successful and wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and further improve its pharmacological properties. Among the recently introduced such multi-action prodrugs is Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, the glycolysis in cancer cells. While platinum based multi-action prodrugs are exhibiting increased levels of activity towards cancer cells and, thus, considered as potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteomes. These are the challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work we performed these analyses for 8-azaguanine and experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780, using both mechanism- and compound-centric chemical proteomics approaches based on ultrafast expression proteomics and thermal proteome profiling, respectively. Analysis of data obtained for Pt(IV)-lonidamine complex revealed regulation of proteins involved in glucose metabolic process associated with lonidamine further supporting the multi-action mechanism of this prodrug action.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Ivan Fedorov

LAB HEAD: Gorshkov Mikhail V.

PROVIDER: PXD058413 | Pride | 2025-05-26

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 576

Similar Datasets

Project description:Platinum drugs (Pt drugs) are one of the most widely used chemotherapy drugs in cancer treatment. Although the cytotoxic and resistant mechanisms of Pt drugs have been thoroughly explored, it remains elusive what factors affect the receptiveness of DNA to Pt drug-induced damage. A large fraction of the genome shows significantly altered Pt drug-induced DNA damage susceptibility in the in vivo nuclear environment in comparison to isolated DNA, which cannot be explained only by the transcriptional status and DNA accessibility of the chromatin regions in vivo. Here, we demonstrate that, besides local chromatin structure, the global nuclear locations of genomic regions play a key role in modulating Pt drug-induced DNA damage susceptibility in vivo. By integrating data from damage-seq experiments with 3D genome structure information we show that the preferential nuclear locations of genomic regions relative to specific nuclear bodies and nuclear compartments can explain patterns of Pt drug DNA damage susceptibility. Thus, our observations are consistent with recent in vitro observations of an enrichment of Pt drugs in biomolecular condensates linked to certain nuclear bodies. Finally, when mapping observed DNA damage-seq signals onto 3D genome structures, we found that the 3D nuclear distribution of Pt-drug induced DNA damage differs in drug resistant cells in comparison to drug sensitve cells. In particular DNA damage increases in gene poor chromatin preferentially located in the lamina compartment, while DNA damage is decreased in gene rich regions preferentially located at nuclear speckles. This change may deter Pt-drug induced DNA damage from more viable gene dense chromatin regions that are crucial for short term cell survival. This observation suggests a selective spatial redistribution of Pt drug action in the nucleus during the emergence of chemoresistance. These observations are relevant for a better understanding of Pt drug action and the development of cancer resistant cells.

			Action	DRS
	032024_8AZ_C_37_1.mzML	Mzml
	032024_8AZ_C_37_1.raw	Raw
	032024_8AZ_C_37_2.mzML	Mzml
	032024_8AZ_C_37_2.raw	Raw
	032024_8AZ_C_37_3.mzML	Mzml

Dataset Information

Study on the mechanism of action of the Pt(IV) complex with lonidamine ligands by ultrafast chemical proteomics

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets