PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS
Open accessAbstract
Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (1 H‐MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD+) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild‐type (WT) and PARP1 knock‐out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. 1 H‐MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD+ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD+ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD+ levels in the temozolomide‐treated group. The combination of rucaparib and temozolomide did not prevent the NAD+ depletion caused by temozolomide treatment. The 1 H‐MRS results show that NAD+ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD+ would be valuable.
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PARP1 inhibitors have limited clinical use because of toxicity.
“They sensitize tumours to DNA damage, but they have limited use due to toxicity223–225.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [224]
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- Authors
- Almeida, G. S., Bawn, C. M., Galler, M., Wilson, I., Thomas, H. D., Kyle, S., Curtin, N. J., Newell, D. R., & Maxwell, R. J.
- Affiliations
- Newcastle University (GB)
- Corresponding author
- Maxwell, Ross J.
- Venue
- NMR in Biomedicine
- Publisher
- Wiley
- Published
- 2017-05-22
- Volume
- 30
- Issue
- 9
- ISSN
- 0952-3480 (ISSN-L)
- 1099-1492
- OpenAlex
- W2619778153
- Cited by
- 16
- References
- 39
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 4
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- NMR in Biomedicine (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Cancer Research UK, MRC and Department of Health (England) (C29821/A10348)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- rucaparib, PARP inhibitors, NAD levels, 1H NMR, PARP1, temozolomide, colorectal cancer, ovarian cancer, liver tissue, DNA repair, drug combination effects
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Humans, Indoles, Liver, NAD, Mice, Knockout, Cell Line, Tumor, Proton Magnetic Resonance Spectroscopy
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