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PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS
Gilberto S Almeida1, Carlo M Bawn1, Martin Galler1
1Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
Abstract:
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.
Insights
Proton magnetic resonance spectroscopy (MRS) can measure nicotinamide adenosine diphosphate (NAD+) levels. This study shows NAD+ levels can serve as a biomarker for PARP inhibitor and methylating agent cancer treatments.
Area of Science:
- Biochemistry
- Oncology
- Medical Imaging
Background:
- Poly(adenosine diphosphate ribose) polymerases (PARPs) are crucial for DNA repair and are targets for cancer therapy.
- PARP inhibitors like rucaparib are under clinical investigation for cancer treatment.
- Identifying reliable biomarkers for treatment response is essential.
Purpose of the Study:
- To investigate the utility of proton magnetic resonance spectroscopy (¹H-MRS) for quantifying nicotinamide adenosine diphosphate (NAD+) levels.
- To assess the potential of NAD+ as a biomarker for the response to PARP inhibitors and methylating agents in cancer treatment.
- To evaluate the impact of rucaparib and temozolomide on NAD+ levels in cancer cell lines and mouse liver tissue.
Main Methods:
- Utilized ¹H-MRS for quantitative analysis of NAD+ spectra in vitro and ex vivo.
- Treated SW620 (colorectal) and A2780 (ovarian) cancer cell lines with rucaparib, temozolomide, or both.
- Treated PARP1 wild-type (WT) and knock-out (KO) mice with rucaparib, temozolomide, or a combination, analyzing liver tissue extracts.
Main Results:
- Both cancer cell lines exhibited increased NAD+ levels after PARP inhibitor treatment compared to temozolomide treatment.
- Rucaparib treatment significantly increased NAD+ levels in PARP1 WT mouse liver compared to controls.
- Temozolomide treatment significantly decreased NAD+ levels in PARP1 WT mouse liver, an effect not mitigated by combination therapy.
Conclusions:
- ¹H-MRS can quantitatively measure NAD+ levels, demonstrating its potential as a biomarker for PARP inhibitor and methylating agent treatments.
- NAD+ levels serve as a responsive biomarker to both rucaparib and temozolomide therapies.
- In vivo ¹H-MRS measurement of NAD+ is suggested as a valuable approach for monitoring treatment response.
