Abstract
We previously reported on a poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated KJ-28d), which increased the death of human ovarian cancer BRCA1-deficient SNU-251 cells. In the present study, we further investigated the antitumor activities of KJ-28d in BRCA-proficient non-small cell lung cancer (NSCLC) cells to expand the use of PARP inhibitors. KJ-28d significantly inhibited the growth of NSCLC cells in vitro and in vivo, and induced DNA damage and reactive oxygen species in A549 and H1299 cells. Combined treatment with KJ-28d and ionizing radiation led to increased DNA damage responses in A549 and H1299 cells compared to KJ-28d or ionizing radiation alone, resulting in apoptotic cell death. Moreover, the combination of KJ-28d plus a DNA-damaging therapeutic agent (carboplatin, cisplatin, paclitaxel, or doxorubicin) synergistically inhibited cell proliferation, compared to either drug alone. Taken together, the findings demonstrate the potential of KJ-28d as an effective anti-cancer therapeutic agent for BRCA-deficient and -proficient cancer cells. KJ-28d might have potential as an adjuvant when used in combination with radiotherapy or DNA-damaging agents, pending further investigations.
Highlights
Lung cancer is one of the most commonly occurring cancers worldwide
Rucaparib, niraparib, and talazoparib targeting PARP1/2 have been approved by the United States Food and Drug Administration (FDA) for the treatment of breast or ovarian cancer in patients harboring homologous recombination (HR) mutations that induce synthetic lethality in the BRCA1 or BRCA2 gene
We assessed whether KJ-28d can inhibit the growth of BRCA-proficient cancer cells
Summary
Lung cancer is one of the most commonly occurring cancers worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 84% of all lung cancers [1]. Rucaparib, niraparib, and talazoparib targeting PARP1/2 have been approved by the United States Food and Drug Administration (FDA) for the treatment of breast or ovarian cancer in patients harboring HR mutations that induce synthetic lethality in the BRCA1 or BRCA2 gene. Evidence is accumulating that PARP inhibitors (PARPi) have therapeutic efficacy in cancer cells with high genomic instability by inducing synthetic lethality of cells with deficient or insufficient DNA repair [14,15,16]. In this scenario, IR, or radiotherapy or cytotoxic chemotherapeutic agents that induce severe DNA damage could lead to insufficient DNA repair in targeted tumor cells. We further investigated the antitumor activity of KJ-28d in BRCA-proficient cell lines, as well as the combination of KJ-28d and DNA damage-inducing radiotherapy or cytotoxic chemotherapeutics in human NSCLC cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
