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GENEVA: Certain anti-cancer drugs also target healthy cells in addition to malignant ones. Its use may be restricted if its effects on the latter are excessively powerful. A team from the University of Geneva (UNIGE) in cooperation with FoRx Therapeutics, based in Basel, has determined the mechanism of action of PARP inhibitors, which are used specifically to treat breast and ovarian cancer in people with the BRCA gene mutation. These inhibitors prevent PARP proteins from performing two distinct functions. Healthy cells are protected while the harmful effect on Carcinogenic cells it keeps inhibiting one of them.
The effectiveness of these treatments will be reinforced by this research, which was published in the journal Nature.
Despite the thousands of lesions that damage our DNA every day, the genome of our cells is particularly stable thanks to a highly efficient repair system. Among the genes that encode repair proteins are BRCA1 and BRCA2 (for BReast CAncer 1 and 2), which are particularly involved in DNA double helix breaks. The presence of mutations in these genes (in approximately 2 in every 1,000 women) can cause failure to repair damaged DNA and considerably increase the risk of developing breast or ovarian cancer (or prostate cancer in men).
PARP inhibitors have been used to treat this type of cancer for about 15 years. PARP proteins can detect breaks or abnormal structures in the DNA double helix. PARPs then temporarily attach to DNA, synthesizing a chain of sugars that acts as an alarm signal to recruit proteins involved in DNA repair. PARP inhibitor-based treatments block these activities and trap the PARP protein in the DNA. So there is no red flag that triggers DNA repair.
This treatment is toxic for rapidly growing cells, such as cancer cells, which generate too many mutations without having time to repair them and are therefore condemned to die. But our bodies also house healthy, fast-growing cells. This is the case, for example, of hematopoietic cells, the source of red and white blood cells, which, as collateral victims, are also massively destroyed by anti-PARP treatments.
The mechanisms by which anti-PARP drugs kill cells (cancer or not) are not well understood. The laboratory of Professor Thanos Halazonetis in the Department of Molecular and Cellular Biology of the Faculty of Sciences of UNIGE, in collaboration with FoRx Therapeutics, has analyzed the mechanisms of action of PARP inhibitors. The scientists used two classes of PARP inhibitors that identically block the enzymatic activity of PARP, that is, the synthesis of the sugar chain that serves as an alarm signal, but do not trap PARP in DNA with the same force. The team observed that both inhibitors kill cancer cells with the same effectiveness, but that the inhibitor that weakly binds PARP to DNA is much less toxic to healthy cells.
“We discovered that PARP not only acts as an alarm signal to recruit DNA repair proteins, but also intervenes when abnormal DNA structures form as a result of collisions between different machineries that read or copy the same portion of DNA,” explains Michalis. . Petropoulos, postdoctoral fellow in the Department of Molecular and Cellular Biology of the Faculty of Sciences of UNIGE and first author of the study.
When anti-PARP treatment is used, this collision prevention warning signal is not activated. These collisions between machinery will cause an increase in DNA lesions, which cannot be repaired in cancer cells because they lack the BRCA repair proteins. The second activity of PARP treatments, which results in tight binding, also known as trapping, of PARPs in DNA, also causes DNA damage that cells must repair. But this repair is not mediated by the BRCA repair proteins, and as a result, both normal and cancer cells die.
”Therefore, we discovered that inhibition of the enzyme activity is sufficient to kill cancer cells, while capture, when PARP is tightly bound to DNA, also kills normal cells and is therefore responsible for the toxicity of these drugs. “This knowledge will allow us to develop safer PARP inhibitors that inhibit the enzymatic activity of PARP without trapping it in the DNA,” summarizes Thanos Halazonetis, director of the study.
The effectiveness of these treatments will be reinforced by this research, which was published in the journal Nature.
Despite the thousands of lesions that damage our DNA every day, the genome of our cells is particularly stable thanks to a highly efficient repair system. Among the genes that encode repair proteins are BRCA1 and BRCA2 (for BReast CAncer 1 and 2), which are particularly involved in DNA double helix breaks. The presence of mutations in these genes (in approximately 2 in every 1,000 women) can cause failure to repair damaged DNA and considerably increase the risk of developing breast or ovarian cancer (or prostate cancer in men).
PARP inhibitors have been used to treat this type of cancer for about 15 years. PARP proteins can detect breaks or abnormal structures in the DNA double helix. PARPs then temporarily attach to DNA, synthesizing a chain of sugars that acts as an alarm signal to recruit proteins involved in DNA repair. PARP inhibitor-based treatments block these activities and trap the PARP protein in the DNA. So there is no red flag that triggers DNA repair.
This treatment is toxic for rapidly growing cells, such as cancer cells, which generate too many mutations without having time to repair them and are therefore condemned to die. But our bodies also house healthy, fast-growing cells. This is the case, for example, of hematopoietic cells, the source of red and white blood cells, which, as collateral victims, are also massively destroyed by anti-PARP treatments.
The mechanisms by which anti-PARP drugs kill cells (cancer or not) are not well understood. The laboratory of Professor Thanos Halazonetis in the Department of Molecular and Cellular Biology of the Faculty of Sciences of UNIGE, in collaboration with FoRx Therapeutics, has analyzed the mechanisms of action of PARP inhibitors. The scientists used two classes of PARP inhibitors that identically block the enzymatic activity of PARP, that is, the synthesis of the sugar chain that serves as an alarm signal, but do not trap PARP in DNA with the same force. The team observed that both inhibitors kill cancer cells with the same effectiveness, but that the inhibitor that weakly binds PARP to DNA is much less toxic to healthy cells.
“We discovered that PARP not only acts as an alarm signal to recruit DNA repair proteins, but also intervenes when abnormal DNA structures form as a result of collisions between different machineries that read or copy the same portion of DNA,” explains Michalis. . Petropoulos, postdoctoral fellow in the Department of Molecular and Cellular Biology of the Faculty of Sciences of UNIGE and first author of the study.
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”Therefore, we discovered that inhibition of the enzyme activity is sufficient to kill cancer cells, while capture, when PARP is tightly bound to DNA, also kills normal cells and is therefore responsible for the toxicity of these drugs. “This knowledge will allow us to develop safer PARP inhibitors that inhibit the enzymatic activity of PARP without trapping it in the DNA,” summarizes Thanos Halazonetis, director of the study.