Abstract
Due to its potent cytotoxicity in BRCA-mutated tumors, synthetic lethality elicited by poly (ADP-ribose) polymerase (PARP) inhibitor gives renewed enthusiasm to researching and developing anti-cancer therapies. Chronic myeloid leukemia (CML) is a type of cancers that starts in certain blood-forming cells of the bone marrow. Here, we showed that poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib could induce a concentration-dependent cytotoxicity in CML cells derived from pediatric patients. During talazoparib treatment, autophagy was markedly activated, which was confirmed by the accumulation of autophagosomes, decrease of SQSTM1 and up-regulation of LC3-II. Inhibition of autophagy by pharmaceutical inhibitor chloroquine or small-interfering RNA siATG5 significantly increased the cytotoxicity of talazoparib in pediatric CML cells and elicited synergistic anti-tumor effect in patient-derived xenograft model. Our data demonstrated that autophagy played a cyto-protective role in talazoparib-treated pediatric CML and co-treatment with talazoparib and autophagy inhibitor could induce synergetic anti-tumor effect, providing novel insights for pediatric CML treatment.
Highlights
(ADP-ribose) polymerases (PARP) played critical roles in a variety of DNA repair processes through sensing single-strand breaks and regulating the subsequent base-excision repair (Fenerty et al 2018; Karzai et al 2018)
Since researchers found that BRAC1/2-mutant tumors were sensitive to poly (ADP-ribose) polymerase (PARP) inhibition a decade ago, several PARP inhibitors olaparib, rucaparib, niraparib and talazoparib have been approved by FDA to treat germline BRCA-mutated advanced ovarian cancer and breast cancer (Sun et al 2017; Zimmer et al 2018)
First we investigated whether inhibition of PARP by talazoparib could induce cytotoxicity in primary Chronic myeloid leukemia (CML) P#1 and P#2 cells in vitro
Summary
(ADP-ribose) polymerases (PARP) played critical roles in a variety of DNA repair processes through sensing single-strand breaks and regulating the subsequent base-excision repair (Fenerty et al 2018; Karzai et al 2018). Blocking PARP leads to the accumulation of single-strand breaks, which will activate homologous recombination repair (Ashworth 2008; Rouleau et al 2010). BRCA1/2 are the critical proteins in homologous recombination and the mutation of BRAC1/2 in tumors may lead to defects in DNA repair (Farmer et al 2005). Since researchers found that BRAC1/2-mutant tumors were sensitive to PARP inhibition a decade ago, several PARP inhibitors olaparib, rucaparib, niraparib and talazoparib have been approved by FDA to treat germline BRCA-mutated advanced ovarian cancer and breast cancer (Sun et al 2017; Zimmer et al 2018). In this article we investigated the anti-tumor effect of PARP inhibitor talazoparib in pediatric CML and the underlying mechanisms
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