Inhibition of PARP

In This Section:

• PARP in Normal Cells
• PARP in Cancer Cells
• Inhibiting PARP
• Self Test

PARP in Normal Cells

When a normal cell's DNA is damaged or mutated, several cellular mechanisms can come into play to detect and repair the alterations. If the DNA is repaired successfully, the cell survives. However, if the DNA cannot be repaired, the cell will undergo a form of cellular suicide called apoptosis rather than risk passing on flawed genetic information to progeny cells.

One protein involved in repairing damaged DNA is poly(ADP ribose) polymerase 1, or PARP1. When a strand of DNA is broken, or nicked, PARP1 moves to the site of damage and becomes activated. It then recruits a team of DNA repair proteins that work together to mend the broken strand of DNA.

PARP in Cancer Cells

Many standard cancer treatments, including many chemotherapy drugs and radiation therapy, damage the DNA of rapidly dividing cancer cells. If PARP is able to help repair the damage caused by these agents, tumor cells may be more likely to survive and grow.

Inhibiting PARP

However, preclinical studies suggest that standard therapies combined with PARP inhibitors may be more effective than standard therapies alone. If cancer cells are exposed to a PARP inhibitor, the protein will be unable to respond when the cell's DNA is damaged by treatments such as chemotherapy. The presence of unrepaired DNA damage will make the cell more likely to undergo apoptosis.

Clinical trials studying PARP inhibitors in combination with standard chemotherapeutic agents in breast cancer are currently under way.

It is also possible that PARP inhibitors could be effective as single agents against tumors with inherent DNA repair defects, such as breast tumors with mutations in the DNA repair proteins BRCA1 or BRCA2. Preclinical studies have shown that breast tumor cells carrying BRCA mutations undergo an arrest of the cell cycle and apoptosis when exposed to PARP inhibitors, whereas cells with normal BRCA proteins survive and continue to grow.

Several PARP inhibitors are currently being tested in clinical trials involving women with BRCA mutation-associated breast cancer.

Self Test

Questions

1. Women whose breast tumors have mutations in BRCA1 or BRCA2 overexpress PARP.
   1. True
   2. False

Answers

1. Correct Answer: b
   1. True - Incorrect.
      There is no evidence that BRCA-mutation-associated tumors have increased expression of PARP. However, it appears that cancer cells with BRCA1 or BRCA2 mutations are more sensitive to PARP inhibitors (i.e., more likely to undergo growth arrest and apoptosis) than cells with normal BRCA1 or BRCA2. This is most likely because the combination of inhibition of PARP and loss of BRCA1 or BRCA2 function results in inactivation of two major forms of DNA repair, making it more difficult for cells to maintain the integrity of their genome and leaving them more vulnerable to apoptosis.
   2. False - Correct.
      There is no evidence that BRCA-mutation-associated tumors have increased expression of PARP. However, it appears that cancer cells with BRCA1 or BRCA2 mutations are more sensitive to PARP inhibitors (i.e., more likely to undergo growth arrest and apoptosis) than cells with normal BRCA1 or BRCA2. This is most likely because the combination of inhibition of PARP and loss of BRCA1 or BRCA2 function results in inactivation of two major forms of DNA repair, making it more difficult for cells to maintain the integrity of their genome and leaving them more vulnerable to apoptosis.