PARP inhibitors - what supplements may help? From Research

Natural compounds, especially polyphenols such as berberine, turmeric, honokiol, resveratrol and EGCG, are potent inhibitors of PARP and, along with Vitamin D and fish oils, can only help PARP-inhibitor drugs. 

PARP-inhibitor use is growing rapIdly. Many oncologists are telling patients not to take supplements with these drugs. But is that really correct? We look at the research. 

What is PARP, and a PARP inhibitor?

PARP 1, or Poly-ADP Ribose Polymerase 1, is an enzyme (a protein) found in all our cells. Polymerases copy a DNA strand, or an RNA strand in this case to help repair a damaged cell. There appear to be more such polymerases in cancer cells than healthy cells and so they may well be a very useful target for drugs. Inhibit the polymerase and the cancer cell dies. 

Researchers first targeted people with a BRCA1 or BRCA2 mutation because these cells were already known to have problems with DNA repair. DNA is typically repaired by a combination of BRCA and PARP, but in BRCA-mutated patients the repair relies far more on PARP alone.  

These mutations were more common in breast cancer (especially TNBC), and ovarian cancer. But approximately 7 per cent of the population can carry these heritable mutations. Another common cancer affected is prostate cancer. Already research has taken place with endometrial cancer (1) and pancreatic cancer (2). Clinical trials are taking place with Olaparib and NSCLC.

But given all cancer cells need to repair and have higher PARP levels, scientists are now looking beyond cancers with heritable mutations. PARP inhibitors could soon be used for many cancers. 

PARP inhibitors (PARPi) are, indeed, promising agents for the therapy of tumours and many metabolic diseases. 

Current PARP inhibitors

Niraparib (Zejula)

Olaparib (Lynparza)

Talazoparib (Talzenna)

Rucaparib (Rubraca)

It should be noted that they each produce very different toxicities and adverse events. Anaemia and fatigue are the most common side-effects across all 4 drugs. All the drugs must be avoided during pregnancy.

What may make PARP inhibitors work better?

1. Vitamin D - the active metabolite of vitamin D, 1alpha, 25-dihydroxy-vitamin D3, is a PARP inhibitor. Both PARP inhibitors and Vitamin D have been demonstrated to exert anti-inflammatory effects in a variety of diseases such as diabetes, arthritis and inflammatory bowel disease (3). Cancer cells also contain higher levels of copper. Research has shown that vitamin D can utilise this copper to sensitise PARP and researchers suggested using vitamin D alongside a PARP inhibitor (4)

2. Turmeric - It has been known for almost a decade that curcumin could affect multiple repair pathways and had the potential to aid a PARP inhibitor (5) and in 2015 it was shown to increase the sensitivity of PARP to a drug inhibitor (6).

3. Resveratrol - this natural compound has been shown to sensitise breast cancer to PARP inhibitor by autophagy and Akt (7).

4. EGCG and turmeric have many pathways in common. They were shown to work together in chronic lymphocytic leukaemia when they were each shown to cause PARP cleavage (8). 

5. Fish oils - in a study with colon cancer, using two different levels of fish oils, researchers saw an increase in cell death, and  decreases in PARP and VEGF, with the conclusion that fish oils help diminish DNA damage and inhibits inflammatory signaling (9).

6. Polyphenols - PARP-1 plays a part in many metabolic diseases; and plant polyphenols can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes. Users of PARP inhibitors should consume a polyphenol-rich diet as polyphenols are PARP inhibitors (10)

7. Honokiol - Honokiol is a Polyphenol from the Mangolia bush. Honokiol, with or without magnol exerted cytotoxicity in Liver cancer cells. It also, like most polyphenols, activated caspase 3 and cleaved PARP in these cells (11). Honokiol unsurprisingly works well with Turmeric to cleave PARP and prevent cancer cell DNA repair(12).

8. Anti-ageniosis drugs - VEGFR3 inhibitors (e.g. Cediranib) down-regulate repair proteins and could improve PARP inhibitors (13).This would imply that Mistletoe, artemisinin, turmeric, honokiol, EGCG, Panax, ginger, resveratrol, and grape seed extract might all help (14)

9. Berberine - This herbal ingredient is known to inhibit EGFR signalling. In several different cell line experiments Berberine was shown to increase the levels of cleavage of PARP (15), it blocks repair systems and increases sensitivity to PARP inhibitors in Ovarian cancer (16)

10. Ginseng - this herb is often used in conjunction with drugs to generate a better anti-cancer response. Yet again, this herb is shown to regulate Caspase 3 and PARP (17)

11. Black Cumin Seed - this has also been shown in several studies to be an inhibitor of PARP-1, Poly [ADP-ribose] polymerase (18).

12. Reducing hypoxia - Eliminating hypoxic tumour cells improves response to PARP inhibitors (19). Researchers concluded that BRCA1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARP inhibitors - eliminating hypoxic tumour cells should enhance the efficacy of PARP therapy. You can do this by exercising, or by using Hyperbaric Oxygen.

13. Atorvastatin - A recent study showed that atorvastatin reduces cell viability and promotes cervical cancer cell apoptosis by inducing the activation of caspase-3 and poly (ADP-ribose) polymerase (PARP) (20). Other research found that Atorvastatin treatment increased cleaved PARP protein expression at dose of 150 uM (21). However, some PARP inhibitor drugs may increase the CoQ10-reducing side-effects of Atorvastatin. And low CoQ10 levels can lead to greater levels of myopathy; and even more cancer advancement.

14. Disulfiram - We also covered research on Disulfiram showing that PARP inhibitor drugs could be blocked from working by the p97 protein, but this could be blocked by Disulfiram, a drug normally used for alcohol addiction.

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References

1. PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives; Lucia Musacchio et al; Cancer Management Res, 2020; 12: 6123–6135.

2. PARP inhibition in treatment of pancreatic cancer; Pascal Hammel et al; Expert Rev Anticancer Ther 2020 Nov;20(11):939-945.

3. Inhibition of poly(adenosine diphosphate-ribose) polymerase by the active form of vitamin D; Jon G Mabley et al; Int J Mol Med; 2007 Jun;19(6):947-52

4. Causing DNA damage and stopping DNA repair – Vitamin D supplementation with Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors may cause selective cell death of cancer cells; Asim Rizvi Imran Naseem; Medical Hyp[otheses Vol 144, Nov 2020

5. Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor; Hideaki Ogiwara et al; Carcinogenesis 2013 Nov;34(11):2486-97.

6. Curcumin enhances poly(ADP-ribose) polymerase inhibitor sensitivity to chemotherapy in breast cancer cells; Young Eun Choi, Eunmi Park, J Nutr Biochem,  2015 Dec;26(12):1442-7.

7. Resveratrol sensitises breast cancer to PARP inhibitor, talazoparib through dual inhibition of AKT and autophagy flux; GaneshPai Bellare, Birija Sankar Patro Biochemical PharmacologyVolume 199, May 2022, 115024

8. Turmeric and green tea: a recipe for B-Chronic Lymphocytic Leukemia; Laura S. Angelo and Razelle Kurzrock; Clin Can Res, 2009 Feb 15; 15(4): 1123–1125.

9. Fish oil suppresses cell growth and metastatic potential by regulating PTEN and NF-κB signaling in colorectal cancer; Shevali Kansal, Archana Bhatnagar, Navneet Agnihotri; PLoS One,  2014 Jan 8;9(1):e84627.

10. PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols; Natalya V. Maluchenko, Alexey V. Feofanov, Vasily M. Studitsky, Int J Mol Sci  2021 Nov; 22(21): 11441

11. Apoptotic and anti-hepato fibrotic effect of honokiol via activation of GSK3β and suppression of Wnt/β-catenin pathway in hepatic stellate cells; Il Ho Lee et al,  Phytother Res, 2021 Jan;35(1):452-462.

12. Honokiol combined with curcumin sensitizes multidrug-resistant human lung adenocarcinoma A549/DDP cells to cisplatin; Mingming Qi et al, Exp Ther Med, 2021 Nov; 22(5): 1301

13. Exploring and comparing adverse events between PARP inhibitors; Christopher J LaFargue et al;  Lancet Oncol, 2019 Jan; 20(1): e15–e28.

14. Natural health products that inhibit angiogenesis: Curr Oncol 2006 Feb; 13(1): 14–26.

15. Berberine inhibits EGFR signaling and enhances the antitumor effects of EGFR inhibitors in gastric cancer; Junxiong Wang et al;  Oncotarget 2016 Nov 15;7(46):76076-76086.

16. Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition;  Hou D, Xu G, Zhang C, Li B, Qin J, Hao X, Liu Q, Zhang X, Liu J, Wei J, Gong Y, Liu Z, Shao C. Cell Death Dis 2017 Oct 5;8(10):e3070.  

17. Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review; Evid Based Comp Alt Medic;  2014; 2014: 168940.

18. Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety: Md. Abdul Hannan et al; Nutrients 2021; Jun; 13(6): 1784.

19. Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models; J Clin Invest 2021 Jun 1;131(11)

20. Atorvastatin suppresses the progression of cervical cancer via regulation of autophagy. Sheng B, Song Y, Zhang J, Li R, Wang Z, Zhu X.  Am J Transl Res. 2020;12(9):5252–68

21. Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro; Hannah M Jones et al,  Am J Canc Res 2017; 7(12): 2478–2490.