Interestingly, binding of Imatinib inside the catalytic domain of PARP-1 also suggests that it has caspase-independent properties in promoting cancer cell deaths.
Although ATM signaling has been widely studied in different types of cancer, its research is still lacking compared with other DDR-involved molecules such as PARP and ATR.
Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) has turned out an innovative approach for cancer therapy due to its involvement in DNA repair pathways.
Detection of a <i>BRCA1</i> or <i>BRCA2</i> pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with the PARP inhibitor therapy for carriers diagnosed with cancer.
Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer.
Differently, however, when evaluating purified wild-type and mutated PARP1, we identified an almost linear relationship between PARPis' inhibiting PARP1 dissociation from DNA and their cytotoxicity in 17 cancer cell lines.
Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors.
In this narrative review we discuss recent findings on the involvement of PARP family members in cancer stem cell biology and the benefit of their inhibition.
Given the highly important role of PARP1 in DNA repair and cancer intervention, this structure presents an attractive opportunity to explore the therapeutic potential of PARP1 inhibition via G-quadruplex DNA targeting.
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated.
It has recently been shown that Ets-1 interacts with two DNA repair enzymes, PARP-1 (poly(ADP-ribose) polymerase 1) and DNA-PK (DNA-dependent protein kinase), through two different domains and that these interactions play a role in cancer.
In conclusion, PBD-based ADC alone or in combination with a PARP inhibitor may have improved therapeutic window in patients with cancer carrying <i>BRCA</i> mutations.
FUND: This work was supported by grants from the National Science Centre, Poland (2013/09/N/NZ5/01831 to DP-T; 2012/05/B/NZ5/01867 to MC), Academy of Finland (254366 to NAR), Moikoinen Cancer Research Foundation (to NAR) and EU PARP Cluster grant (UDA-POIG.05.01.00-005/12-00/NCREMFP to SW).