PXD052256

PXD052256 is an original dataset announced via ProteomeXchange.

Title	1,4-napthoquinone-sulfomethylene-glucose conjugates, a novel targeted approach for advanced prostate cancer
Description	Rationale: The Warburg effect is a shift from oxidative phosphorylation to aerobic glycolysis accompanied by an enormous increase in glucose uptake into the cancer cell. We have utilized this effect to design a new group of targeted cytotoxic 1,4-naphthoquinones. To optimize the compounds for clinical use, a group of 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker was synthesized and comprehensively evaluated. Methods: Screening experiments for efficacy and selectivity were performed in a newly synthesized library of 32 conjugates. For the most promising compound PeS-9 activity and mode of action were determined in in vitro, ex vivo and in vivo experiments using different models for prostate cancer (PCa) including human cell lines with various resistance profiles as well as patients-derived tumoroids. Additional experiments were carried out to determine the stability of PeS-9 in the blood as well as possible side effects. Results: The screening experiments identified PeS-9 to have a high efficacy in combination with a promising selectivity towards PCa cells. Further testing of hit compound PeS-9 revealed a selective cytotoxic activity conditioned by a GLUT-1-mediated uptake. PeS-9 induced androgen receptor degradation followed by downregulation of its signaling. In addition, increased reactive oxygen species production and enhanced DNA double-strand breaks were observed. Combinational therapy with PARP-inhibitor olaparib resulted in synergistic effects in homologous recombination deficient cells. The underlying mode of PeS-9 cytotoxic action involved mitochondria targeting, leading to a loss of mitochondrial membrane potential, release of cytochrome C and AIF, activation of caspases-3 and -9, PARP cleavage and apoptotic cell death. This process was stipulated by down-regulation of several antiapoptotic factors and induction of endoplasmic reticulum stress. Moreover, drug-induced activation of signaling pathway mediated by kinases p38, JNK1/2, and ERK1/2 was identified as important factor of the cytotoxic activity. The anticancer activity of PeS-9 could be confirmed ex vivo using patients-derived tumoroids as well as in vivo resulting in decreased tumor growth and dissemination of PCa cells to the lungs. No serious side effects were observed in animal models. In human blood, PeS-9 was more stable than the mother compound. Conclusion: In conclusion, we were able to synthesize and characterize PeS-9, a new 1,4-naphthoquinones-glucose derivative conjugated via a thiomethylene linker. This novel targeted approach exhibited potent antitumor activity and selectivity in human PCa cells mediated by the Warburg effect. The simultaneous inhibition of the AR signaling pathway in combination with increased production of reactive oxygen species make it an attractive substance both as a monotherapy and as a combination partner, especially with PARP inhibitors.
HostingRepository	PRIDE
AnnounceDate	2025-04-14
AnnouncementXML	Submission_2025-04-14_05:09:49.015.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Mair
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-14 04:58:24	ID requested
⏵ 1	2025-04-14 05:09:49	announced

Dataset with its publication pending

submitter keyword: 1, castration-resistant prostate cancer, combinational therapy.,4-naphthoquinone, ROS, mitochondria, Warburg effect, apoptosis

Sergey Dyshlovoy
contact affiliation	Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
contact email	s.dyshlovoy@uke.de
lab head
Thomas Mair
contact affiliation	Section for Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf
contact email	t.mair@uke.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD052256
     1. Label: PRIDE project
     2. Name: 1,4-napthoquinone-sulfomethylene-glucose conjugates, a novel targeted approach for advanced prostate cancer