Dataset Information

Determine PARP1 and PARP2 target engagment of Niraparib and Olaparib in live cells

ABSTRACT: Determine the target engagment of PARP inhibitors (Niraparib and Olaparib) to PARP1 and PAPR2 in live cells using isothermal dose-response experiments

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF-X, Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Uwb1.289 Cell, Cell Line Cell

SUBMITTER: Maria Faelth Savitski

LAB HEAD: Marcus Bantscheff

PROVIDER: PXD044332 | Pride | 2025-05-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	03488_F1_R1_P0298687B01_TMTPRO16.raw.gz	Raw
	03488_F1_R1_P0298687B02_TMTPRO16.raw.gz	Raw
	03488_F1_R1_P0298687B03_TMTPRO16.raw.gz	Raw
	03488_F1_R1_P0298687B04_TMTPRO16.raw.gz	Raw
	03488_F1_R1_P0298687B05_TMTPRO16.raw.gz	Raw

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Publications

Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation.

Rutkowska Anna A Eberl H Christian HC Werner Thilo T Hennrich Marco L ML Sévin Daniel C DC Petretich Massimo M Reddington James P JP Pocha Shirin S Gade Stephan S Martinez-Segura Amalia A Dvornikov Dmytro D Karpiak Joel J Sweetman Gavain M A GMA Fufezan Christian C Duempelfeld Birgit B Braun Florian F Schofield Christopher C Keles Hakan H Alvarado David D Wang Zhuo Z Jansson Keith H KH Faelth-Savitski Maria M Curry Edward E Remlinger Katja K Stronach Euan A EA Feng Bin B Sharma Geeta G Coleman Kevin K Grandi Paola P Bantscheff Marcus M Bergamini Giovanna G

Cancer research communications 20240901 9

An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP ...[more]

PMID: 39028932

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Project description:Rationale: Optimal intratumor distribution of an anticancer drug is fundamental to reach an active concentration in neoplastic cells, ensuring the therapeutic effect. Determination of drug concentration in tumor homogenates by LC-MS/MS gives important information about this issue but the spatial information gets lost. Targeted mass spectrometry imaging (MSI) has great potential to visualize drug distribution in the different areas of tumor sections, with good spatial resolution and superior specificity. MSI is rapidly evolving as a quantitative technique to measure the absolute drug concentration in each single pixel. Methods: Different inorganic nanoparticles were tested as matrices to visualize the PARP inhibitors (PARPi) niraparib and olaparib. Normalization by deuterated internal standard and a custom preprocessing pipeline were applied to achieve a reliable single pixel quantification of the two drugs in human ovarian tumors from treated mice. Results: A quantitative method to visualize niraparib and olaparib in tumor tissue of treated mice was set up and validated regarding precision, accuracy, linearity, repeatability and limit of detection. The different tumor penetration of the two drugs was visualized by MSI and confirmed by LC-MS/MS, indicating the homogeneous distribution and higher tumor exposure reached by niraparib compared to olaparib. On the other hand, niraparib distribution was heterogeneous in an ovarian tumor model overexpressing the multidrug resistance protein P-gp, a possible cause of resistance to PARPi. Conclusions: The current work highlights for the first time quantitative distribution of PAPRi in tumor tissue. The different tumor distribution of niraparib and olaparib could have important clinical implications. These data confirm the validity of MSI for spatial quantitative measurement of drug distribution providing fundamental information for pharmacokinetic studies, drug discovery and the study of resistance mechanisms.