Poly (ADP-ribose) polymerase and its role in cancer in combination with 2-deoxyglucose (2DG) -

PARP is a family containing many proteins that have important functions in the cell like the stability of the genome, repair of damaged DNA, and apoptosis or programmed cell death.

 

PARP family members

There are 17 proteins in this family. PARP 1 was the first protein from this family that was studied in detail. It was observed that it has an important role in DNA repair processes in cells. PARP 2 and PARP-3 are involved in the synthesis of branched polymers. Similarly, other members have also many important functions in the cells. The PARP family proteins are upregulated in the tumor cells usually after the primary treatment as the cells have to repair the damages caused to their nucleic acids by radiations or drugs.

 

The normal function of PARP in cell

PARP family proteins are involved in the recognition and repair of any damage to the DNA in a cell. This damage in the DNA may be induced by any internal or external factor in the cell. It may result from some chemical, radiation, or metabolic mutagen. The PARP family recognizes this damage and activates the repair machinery in the cell.

When PARP recognizes the damage induced in DNA by any mutagen, it will bind the ss DNA at the position where damage has occurred and start the synthesis of adenine nucleotides there. This addition of A nucleotides in a chain is also called a poly ADP ribose chain. This PAR will attract the enzymes for DNA repair to this site. These enzymes may be DNA polymerase beta, DNA ligase enzyme, and some scaffolding proteins. All these will help in the repair of single-stranded DNA molecules. After the damage is repaired, PARP will be degraded by another enzyme, PAR glycohydrolase (Jubin et al., 2016).

 

Role of PARP in Cancer

PARP plays a very crucial role in the stimulation and progression of carcinogenesis. Many experiments have shown that PARP family of proteins is involved in modifying the cancerous phenotype of cells. It not only helps in repair of DNA damages caused by radiation or alkylating agents but also helps in epigenetic modifications of many proteins and protein-protein interactions in cancer cells.

Most cancer cells lack DNA repair processes. When radiotherapy or chemotherapy is given to the cancer cells. DNA damage is caused in them. This will cause a reduction of tumors in the patient.

But activated PARP family in the tumor cells will help them recover the damage caused by these therapies. And the tumor will recur in the body of the patient after the damage is repaired. So, targeting PARP in tumor cells by using some inhibitors can be an effective therapy (Patel et al., 2020).

 

PARP inhibitors

PARP inhibitors have been proven to be an effective therapeutic modality against cancer cells. As mentioned earlier, PARP plays an important role in DNA repair. If PARP is inhibited in the cell, then the damage to DNA molecules caused by radiation or drugs will not be repaired. As cancer cells lack the processes like homologous repair. So, there is no way of repair in the cells, and this will lead to the death of cells. Hence, the use PARP inhibitors like Olaparib can be used to treat cancer patients. This is most effective in the case of breast and ovarian cancers in females.

Olaparib

The first PARP inhibitor that was approved by FDA and first used for cancer patients in Europe is Olaparib. It was found experimentally that Olaparib has antitumor activity in patients with breast or ovarian cancers. As it targets PARP and inhibits the repair of DNA in these cells. This will reduce the size of the tumor by killing the cancerous cells that lack the homologous recombination process of DNA repair.

Clinical trials were performed to check the efficacy of Olaparib. 400mg of the drug was given twice a day to the patients and was found to be highly effective against certain types of cancers.

Moreover, the patients were given chemotherapy first. And the use of Olaparib reduced the chances of recurrence of cancer in these patients later on (Bell et al., 2011).

 

Relation between PARP and 2DG

2DG is a glycolytic inhibitor that has structural similarity with the glucose molecule. It can bind the glucose transporters but can not be metabolized. When 2DG is given to the tumor cells, it makes them deficient in energy by inhibiting the process of glycolysis. As most of the tumor cells depend on ATP energy produced by glycolysis. So, the cells will be totally deprived of energy and will not be able to survive anymore.

If a patient is given primary tumor treatment like surgery followed by chemotherapy or radiotherapy and is treated with 2DG. This will stop the recurrence of the tumor in that patient. Moreover, if a PARP inhibitor is also given to the patient, this will also help inhibit tumor recurrence (Richard et al., 2022).

So, the use of 2DG and PARP inhibitors both can reduce tumor progression and recurrence in patients.

The PARP family of proteins needs the energy to work in DNA repair. If 2DG is given to the tumor cells makes them deficient in energy, this will not allow the PARP family of proteins to perform their proper function of DNA repair in these cells.

 

Can 2DG and PARP inhibitors be taken together?

Experiments were performed on breast cancer patients to check the effectiveness of combination therapy for PARP inhibitors and 2DG. It was observed that PARP inhibitors upregulate the expression of Programmed Death Ligand-1 (PDL-1) in the tumor cells. PDL-1 is highly glycosylated in the case of tumor cells. These experiments were performed on triple-negative breast cancer patients, its been seen deglycosylation of PD-L1 by 2-deoxyglucose reverses PARP inhibitor-induced immunosuppression in triple-negative breast cancer

Glycosylated PD-L1, the functional form of PD-L1, is required for PD-L1-PD-1 interaction. TNBC cells have significantly higher levels of glycosylated PD-L1.  2-deoxyglucose (2-DG) can act as a glucose analog to decrease PD-L1 glycosylation. Because PARP inhibition upregulates PD-L1, 2-DG reduced PARP inhibition-mediated expression of glycosylated PD-L1. The combination of PARP inhibition and 2-DG had potent anti-tumor activity.

 

If 2DG is given to such patients, it was observed that it will cleave the PARP family of proteins, thus resulting in non-functional proteins. They will not be able to help the cells repair the damage in their DNA.

So, if the tumors are treated with any conventional therapy like chemotherapy or radiation therapy and are given PARP inhibitors like Olaparib, rucaparib, or niraparib, and are also treated with 2DG that is a glucose analog and inhibitor of glycolysis in tumor cells. Both these drugs will result in the death of cancer cells and will stop the recurrence of tumors in such patients (Demény & Virág, 2021).

Olaparib will inhibit the PARP family of proteins and 2DG will also cleave PARP, thus both drugs will inhibit the repair processes in cells resulting in the killing of cells by radiations or chemicals. So, we can say that PARP inhibitors and 2DG are agonists to each other working in the same way.

 

Conclusion

PARP is a large family of proteins that play many important roles in the cells. One of the most crucial roles of this family is to help in DNA repair in cells. Cancer cells have exposure to radiation or chemicals that can cause breaks in DNA. So, they need to repair these breaks in order to survive. PARP is upregulated in cancer cells, so targeting it will be an effective therapy to treat cancer patients, especially those with ovarian and breast cancer.2DG is also an important drug against many types of cancers. It is proved experimentally that 2DG cleaves PARP and can be given along with PARP inhibitors to stop the recurrence and progression of cancer in patients.

 

References

Bell, E., Patel, D., Palanichamy, K., & Chakravarti, A. (2011). Effects of PTEN Status on Poly (ADP-ribose) Polymerase Inhibition in Addition to Radiation and Temozolomide in Glioblastoma. International Journal of Radiation Oncology*Biology*Physics, 81(2), S753. https://doi.org/10.1016/j.ijrobp.2011.06.1251 https://www.frontiersin.org/articles/10.3389/fcell.2021.801200/full

 

Demény, M. A., & Virág, L. (2021). The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions. Cancers, 13(9), 2057. https://www.mdpi.com/2072-6694/13/9/2057 https://sci-hub.hkvisa.net/10.3390/cancers13092057

 

Jubin, T., Kadam, A., Jariwala, M., Bhatt, S., Sutariya, S., Gani, A. R., Gautam, S., & Begum, R. (2016). The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival. Cell Proliferation, 49(4), 421–437. https://doi.org/10.1111/cpr.12268 https://sci-hub.hkvisa.net/10.1111/cpr.12268

 

Patel, M., Nowsheen, S., Maraboyina, S., & Xia, F. (2020). The role of poly(ADP-ribose) polymerase inhibitors in the treatment of cancer and methods to overcome resistance: A review. Cell and Bioscience, 10(1), 1–12. https://doi.org/10.1186/s13578-020-00390-7

Richard, I. A., Burgess, J. T., O’Byrne, K. J., & Bolderson, E. (2022). Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics. Frontiers in Cell and Developmental Biology, 9(January), 1–11. https://doi.org/10.3389/fcell.2021.801200 https://www.redjournal.org/action/showPdf?pii=S0360-3016%2811%2902072-4

Tags: 2-deoxyglucose (2DG), angiogenesis, Blog, cancer, cancer treatment, poly (ADP-ribose) polymerase

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