ABSTRACT
Several in vitro studies have confi rmed that inhibition of PARP in a BRCAdefi cient background results in synthetic lethality (Bryant et al. 2005; Farmer et al. 2005). Initial reports showed that the Chinese hamster BRCA2defi cient cell line V-C8 was hypersensitive to low concentrations of PARP inhibitors (NU1025 and AG14361) as compared to wild-type cells; this effect was lost with BRCA2 complementation, demonstrating its specifi city for BRCA2 (Bryant et al. 2005). Brca1-/- and Brca2-/- mouse embryonic stem cells were also identifi ed as being sensitive to PARP inhibitors (KU0058684 and KU0058948), which induced chromosomal aberrations that led to cell cycle arrest and apoptosis, supporting the hypothesis that PARP inhibitors cause the accumulation of DSBs in BRCA-defi cient cells (Farmer et al. 2005). Experiments in mice showed that BRCA2-defi cient xenografts had reduced tumor growth when treated with PARP inhibitors, while BRCA2 complemented xenografts treated with PARP inhibitors saw no reduction in growth (Bryant et al. 2005). Additionally, the human breast cancer cell lines MCF7 (p53 WT) and MDA-MB-231 (p53 mutant) were very sensitive to the PARP inhibitor NU1025 when BRCA2 was specifi cally depleted by siRNA, demonstrating that this effect is independent of p53 status (Bryant et al. 2005). Though PARP inhibitors block both PARP1 and PARP2, experiments using siRNA depletion of PARP1 or PARP2, each with simultaneous BRCA2 depletion, suggested that PARP1 (and not PARP2) was responsible for the synthetic lethal effect (Bryant et al. 2005). Interestingly, siRNA depletion of PARP1 was not as effective for synthetic lethality as the PARP inhibitors, perhaps due to incomplete siRNA depletion (Bryant et al. 2005). Alternatively, it has been suggested that inhibiting PARP activity without inhibiting its DNA binding causes inactive PARP to accumulate at DNA breaks, resulting in a more toxic lesion (Bryant et al. 2005).
