What are the potential adverse effects of PARP inhibitors?5 answersPARP inhibitors can lead to various adverse effects. These include hematological toxicity, gastrointestinal issues, fatigue, hypertension, hypertensive crisis, palpitations, and thromboembolic events. Notably, hematologic toxicity and gastrointestinal symptoms are common class effects of PARP inhibitors, with some patients experiencing anemia and gastrointestinal reactions. Patients with BRCA mutations, who are often treated with PARP inhibitors, are more prone to severe adverse effects, leading to dose adjustments or treatment discontinuation, emphasizing the need for careful monitoring and management of side effects in this population. Regular monitoring, timely symptomatic treatment, and multidisciplinary consultations are crucial in mitigating the risks associated with PARP inhibitor-related adverse reactions.
How do PARP inhibitors enhance the efficacy of natural chemotherapeutics in cancer treatment?5 answersPARP inhibitors enhance the efficacy of natural chemotherapeutics in cancer treatment by targeting DNA repair pathways crucial for cancer cell survival. These inhibitors induce DNA damage, leading to genomic instability and cell death, particularly in BRCA1/BRCA2-mutant tumors. However, cancer cells can develop resistance to PARP inhibitors over time. To overcome this resistance, co-administration of natural P-glycoprotein (P-gp) inhibitors with chemotherapeutics can enhance cellular drug concentrations. Utilizing nanotechnology for co-delivery of these agents improves drug retention within cancer cells, thereby increasing the anticancer potential of chemotherapeutics. This combined approach presents a promising strategy to combat multidrug resistance and improve the effectiveness of cancer treatment regimens.
What is known about the role of PARP1 in DNA double-strand break repair?4 answersPARP1 is a nuclear protein involved in the maintenance of genomic stability. It catalyzes the formation of poly(ADP-ribose) (PAR) to recruit repair proteins at the site of DNA lesions, such as double-strand breaks. PARP1 is also a DNA-dependent ADP-Ribose transferase that is triggered by DNA breaks to mediate their resolution. PARP1 plays a crucial role in repairing DNA damage and modifying proteins, and its activity increases on DNA binding. PARP1 is recruited to stalled replication forks to restrain DNA replication and prevent fork collapse. PARP1 interacts directly with DJ-1, a protein involved in DNA double-strand break repair, and stimulates its enzymatic activity during DNA repair. Overall, PARP1 is involved in the recognition and repair of DNA double-strand breaks, and its activity is crucial for maintaining genomic stability.
How do PARP inhibitors work?4 answersPARP inhibitors (PARPi) work by inhibiting PARP proteins involved in DNA damage repair. This leads to the accumulation of DNA damage and triggers cell death through a process called synthetic lethality. PARPi specifically target cells with deficiencies in homologous recombination repair (HRR), such as those with BRCA1/BRCA2 mutations. By blocking the repair of single-strand DNA breaks and interfering with the HR pathway, PARPi induce a synergistic lethal effect, resulting in the death of tumor cells. The effectiveness of PARPi has been demonstrated in various cancers, including ovarian, breast, prostate, and pancreatic cancers. However, resistance to PARPi can develop, and research is ongoing to understand and overcome these resistance mechanisms. Overall, PARP inhibitors offer a targeted therapeutic option for cancer treatment by exploiting DNA repair vulnerabilities in tumor cells.
How do PARP inhibitors affect LINE-1 expression in cancer cells?5 answersPARP inhibitors have been shown to increase the expression of Type I interferon (IFN) regulated genes in cancer cells. In particular, the PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) consistently promote the expression of IFN Type I regulated genes, while the mainly catalytic inhibitor veliparib has little to no effect on the expression of these genes. Additionally, PARP inhibitors have been found to have immunomodulatory properties, including the activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway and the downstream type I IFN signaling. However, there is no specific information available regarding the effect of PARP inhibitors on LINE-1 expression in cancer cells in the provided abstracts.
Do parp inhibitors show efficacy in FANCD2 defective tumors?4 answersPARP inhibitors have shown efficacy in FANCD2 defective tumors. Loss of BRCA1/2 proteins, which function in homologous recombination (HR)-mediated DNA repair, leads to DNA repair deficiency and replicative stress. BRCA1/2-deficient tumors upregulate FANCD2 activity, which is required for fork protection and fork restart in these tumors. FANCD2 also promotes Polθ recruitment at sites of damage and alternative end-joining (alt-EJ) repair. Loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These findings suggest a synthetic lethal relationship between FANCD2 and BRCA1/2, and highlight the role of FANCD2 in orchestrating DNA repair pathway choice at the replication fork. Therefore, PARP inhibitors may show efficacy in FANCD2 defective tumors due to the upregulation of FANCD2 activity in these tumors.