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DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition.

ABSTRACT: The overall prognosis for pancreatic cancer remains dismal and potent chemotherapeutic agents that selectively target this cancer are critically needed. Elevated expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is frequent in pancreatic cancer, and it offers promising tumor-selective targeting. Recently, KP372-1 was identified as a novel NQO1 redox cycling agent that induces cytotoxicity in cancer cells by creating redox imbalance; however, the mechanistic basis of KP372-1-induced cytotoxicity remains elusive. Here, we show that KP372-1 sensitizes NQO1-expressing pancreatic cancer cells and spares immortalized normal pancreatic duct cells, hTERT-HPNE. Notably, we found that KP372-1 is ~?10- to 20-fold more potent than ?-lapachone, another NQO1 substrate, against pancreatic cancer cells. Mechanistically, our data strongly suggest that reactive oxygen species produced by NQO1-dependent redox cycling of KP372-1 cause robust DNA damage, including DNA breaks. Furthermore, we found that KP372-1-induced DNA damage hyperactivates the central DNA damage sensor protein poly(ADP-ribose) polymerase 1 (PARP1) and activates caspase-3 to initiate cell death. Our data also show that the combination of KP372-1 with PARP inhibition creates enhanced cytotoxicity in pancreatic cancer cells. Collectively, our study provides mechanistic insights into the cytotoxicity instigated by KP372-1 and lays an essential foundation to establish it as a promising chemotherapeutic agent against cancer.

SUBMITTER: Viera T

PROVIDER: S-EPMC7677541 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition.

Viera Talysa T Patidar Praveen L PL

Scientific reports 20201119 1

The overall prognosis for pancreatic cancer remains dismal and potent chemotherapeutic agents that selectively target this cancer are critically needed. Elevated expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is frequent in pancreatic cancer, and it offers promising tumor-selective targeting. Recently, KP372-1 was identified as a novel NQO1 redox cycling agent that induces cytotoxicity in cancer cells by creating redox imbalance; however, the mechanistic basis of KP372-1-induced cytotoxic ...[more]

PMID: 33214574

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Project description:Background: Oncogenic transformation is associated with elevated oxidative stress that promotes tumor progression but also renders cancer cells vulnerable to further oxidative insult. Agents that stimulate ROS generation or suppress antioxidant systems can drive oxidative pressure to toxic levels selectively in tumor cells, resulting in oxidative DNA damage to endanger cancer cell survival. However, DNA damage response signaling protects cancer cells by activating DNA repair and genome maintenance mechanisms. In this study, we investigated the synergistic effects of combining the pro-oxidative natural naphthoquinone alkannin with inhibition of DNA repair by PARP inhibitors. Methods and Results: The results showed that sublethal doses of alkannin induced ROS elevation and oxidative DNA damage in colorectal cancer but not normal colon epithelial cells. Blocking DNA repair with the PARP inhibitor olaparib markedly synergized with alkannin to yield synergistic cytotoxicity in colorectal cancer cells at nontoxic doses of both drugs. Synergy between alkannin and olaparib resulted from interrupted repair of alkannin-induced oxidative DNA damage and PARP-trapping, as it was significantly attenuated by NAC or by OGG1 inhibition and the non-trapping PARP inhibitor veliparib did not yield synergism. Mechanistically, the combination of alkannin and olaparib caused intense replication stress and DNA strand breaks in colorectal cancer cells, leading to apoptotic cancer cell death after G2 arrest. Consequently, coadministration of alkannin and olaparib induced significant regression of tumor xenografts in vivo, while each agent alone had no effect. Conclusion: These studies clearly show that combining alkannin and olaparib can result in synergistic cancer cell lethality at nontoxic doses of the drugs. The combination exploits a cancer vulnerability driven by the intrinsic oxidative pressure in most cancer cells and hence provides a promising strategy to develop broad-spectrum anticancer therapeutics.

Project description:BackgroundCervical cancer is one of the most common cancers among females worldwide and advanced patients have extremely poor prognosis. However, adverse reactions and accumulating resistance to radiation therapy require further investigation.MethodsThe expression levels of mitogen-activated protein kinase 4 (MAPK4) mRNA were analyzed by real-time PCR and its association with overall survival was analyzed using Kaplan-Mier method. Colony formation, immunofluorescence and western blotting were used to examine the effects of MAPK4 knockout or over-expression on cervical cancer cells after radiation treatment. Drug-sensitivity of cervical cancer cells to PARP1 inhibitors, olaparib or veliparib, was analyzed by CCK-8 cell viability assays, and the 50% inhibitory concentration (IC50) was quantified using GraphPad Prism. The functional effects of MAPK4 knockout on the sensitivity of cervical cancer to radiation treatment and PARP1 inhibitors were further examined using xenograft tumor mouse models in vivo.ResultsCervical cancer patients with high MAPK4 mRNA expression have lower survival rate. After radiation treatment, the colony number of MAPK4 knockout cells was markedly reduced, and the markers for DNA double-chain breakage were significantly up-regulated. In addition, MAPK4 knockout reduced protein kinase B (AKT) phosphorylation, whereas its over-expression resulted in opposite effects. In MAPK4 KO cells with irradiation treatment, inhibition of AKT phosphorylation promoted DNA double-chain breakage. Constitutive activation of AKT (CA-AKT) increased the levels of phosphorylated-AKT (p-AKT), and DNA repair-related proteins, phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). Furthermore, MAPK4 knockout was found to affect the sensitivity of cervical cancer cells to poly ADP-ribose polymerase 1 (PARP1) inhibitors by activating the phosphorylation of AKT. Moreover, in vivo results demonstrated that MAPK4 knockout enhanced the sensitivity of cervical cancer to radiation and PARP1 inhibitors in mouse xenograft models.ConclusionsCollectively, our data suggest that combined application of MAPK4 knockout and PARP1 inhibition can be used as therapeutic strategy in radiation treatment for advanced cervical carcinoma.

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DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition.

Publications

DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition.

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