scholarly journals The mechanism of cancer cell death by PARP inhibitors goes beyond DNA damage alone

2019 ◽  
Vol 145 (9) ◽  
pp. 2594-2596
Author(s):  
Antonio Macciò ◽  
Clelia Madeddu
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cell ◽  
Parp Inhibitors ◽  
Cancer Cell Death

scholarly journals DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1593 ◽  
Author(s):  
Nicolas Malaquin ◽  
Arthur Vancayseele ◽  
Sophie Gilbert ◽  
Laureen Antenor-Habazac ◽  
Marc-Alexandre Olivier ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Fate ◽  
Cancer Cell ◽  
Parp Inhibitors ◽  
Model Systems ◽  
Dependent Manner ◽  
Systematic Analysis ◽  
Context Dependent

Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.

New Fe(iii) and Co(ii) salen complexes with pendant distamycins: selective targeting of cancer cells by DNA damage and mitochondrial pathways

2016 ◽  
Vol 45 (22) ◽  
pp. 9345-9353 ◽  
Author(s):  
Asfa Ali ◽  
Mohini Kamra ◽  
Arunoday Bhan ◽  
Subhrangsu S. Mandal ◽  
Santanu Bhattacharya
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Metal Complexes ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Cell Death ◽  
Salen Complexes ◽  
Selective Targeting

Distamycin like moieties conjugated with core Fe(iii) and Co(ii) based salens were synthesized and studied. The metal complexes showed better and differential activity toward cancer cell death.

scholarly journals Canady Helios Cold Plasma Induces Breast Cancer Cell Death by Oxidation of Histone mRNA

2021 ◽  
Vol 22 (17) ◽  
pp. 9578
Author(s):  
Xiaoqian Cheng ◽  
Saravana R. K. Murthy ◽  
Taisen Zhuang ◽  
Lawan Ly ◽  
Olivia Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cancer Cell ◽  
Cold Plasma ◽  
S Phase ◽  
Histone Mrna ◽  
Cancer Cell Death ◽  
Marker Status

Breast cancer is the most common cancer among women worldwide. Its molecular receptor marker status and mutational subtypes complicate clinical therapies. Cold atmospheric plasma is a promising adjuvant therapy to selectively combat many cancers, including breast cancer, but not normal tissue; however, the underlying mechanisms remain unexplored. Here, four breast cancer cell lines with different marker status were treated with Canady Helios Cold Plasma™ (CHCP) at various dosages and their differential progress of apoptosis was monitored. Inhibition of cell proliferation, induction of apoptosis, and disruption of the cell cycle were observed. At least 16 histone mRNA types were oxidized and degraded immediately after CHCP treatment by 8-oxoguanine (8-oxoG) modification. The expression of DNA damage response genes was up-regulated 12 h post-treatment, indicating that 8-oxoG modification and degradation of histone mRNA during the early S phase of the cell cycle, rather than DNA damage, is the primary cause of cancer cell death induced by CHCP. Our report demonstrates for the first time that CHCP effectively induces cell death in breast cancer regardless of subtyping, through histone mRNA oxidation and degradation during the early S phase of the cell cycle.

Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4-d]pyrimidine nucleoside derivatives-induced cancer cell death

2009 ◽  
Vol 29 (6) ◽  
pp. 489-495 ◽  
Author(s):  
Hai-liang Liu ◽  
Jing-jing Xu ◽  
Xiao-min Dai ◽  
Jing-Bo Shi ◽  
Song Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Cancer Cell ◽  
Pyrimidine Nucleoside ◽  
Cancer Cell Death

Guanidine-reactive agent phenylglyoxal induces DNA damage and cancer cell death

2012 ◽  
Vol 64 (6) ◽  
pp. 1515-1525 ◽  
Author(s):  
José M. Calderón-Montaño ◽  
Estefanía Burgos-Morón ◽  
Manuel L. Orta ◽  
Nuria Pastor ◽  
Concepción Perez-Guerrero ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cell ◽  
Cancer Cell Death

Alpha, beta-unsaturated lactones 2-furanone and 2-pyrone induce cellular DNA damage, formation of topoisomerase I- and II-DNA complexes and cancer cell death

2013 ◽  
Vol 222 (1) ◽  
pp. 64-71 ◽  
Author(s):  
José Manuel Calderón-Montaño ◽  
Estefanía Burgos-Morón ◽  
Manuel Luis Orta ◽  
Nuria Pastor ◽  
Caroline A. Austin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cell ◽  
Topoisomerase I ◽  
Dna Complexes ◽  
Cancer Cell Death ◽  
Alpha Beta ◽  
Unsaturated Lactones ◽  
Cellular Dna

scholarly journals An Interaction with PARP-1 and Inhibition of Parylation Contribute to Attenuation of DNA Damage Signaling by the Adenovirus E4orf4 Protein

2019 ◽  
Vol 93 (19) ◽  
Author(s):  
Keren Nebenzahl-Sharon ◽  
Rakefet Sharf ◽  
Jana Amer ◽  
Hassan Shalata ◽  
Hanan Khoury-Haddad ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cell ◽  
Virus Replication ◽  
Parp Inhibitor ◽  
Dependent Manner ◽  
Drug Induced ◽  
Cancer Cell Death ◽  
Dna Damage Signaling ◽  
Parp 1

ABSTRACT The adenovirus (Ad) E4orf4 protein was reported to contribute to inhibition of ATM- and ATR-regulated DNA damage signaling during Ad infection and following treatment with DNA-damaging drugs. Inhibition of these pathways improved Ad replication, and when expressed alone, E4orf4 sensitized transformed cells to drug-induced toxicity. However, the mechanisms utilized were not identified. Here, we show that E4orf4 associates with the DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP-1) and that the association requires PARP activity. During Ad infection, PARP is activated, but its activity is not required for recruitment of either E4orf4 or PARP-1 to virus replication centers, suggesting that their association occurs following recruitment. Inhibition of PARP-1 assists E4orf4 in reducing DNA damage signaling during infection, and E4orf4 attenuates virus- and DNA damage-induced parylation. Furthermore, E4orf4 reduces PARP-1 phosphorylation on serine residues, which likely contributes to PARP-1 inhibition as phosphorylation of this enzyme was reported to enhance its activity. PARP-1 inhibition is important to Ad infection since treatment with a PARP inhibitor enhances replication efficiency. When E4orf4 is expressed alone, it associates with poly(ADP-ribose) (PAR) chains and is recruited to DNA damage sites in a PARP-1-dependent manner. This recruitment is required for inhibition of drug-induced ATR signaling by E4orf4 and for E4orf4-induced cancer cell death. Thus, the results presented here demonstrate a novel mechanism by which E4orf4 targets and inhibits DNA damage signaling through an association with PARP-1 for the benefit of the virus and impacting E4orf4-induced cancer cell death. IMPORTANCE Replication intermediates and ends of viral DNA genomes can be recognized by the cellular DNA damage response (DDR) network as DNA damage whose repair may lead to inhibition of virus replication. Therefore, many viruses evolved mechanisms to inhibit the DDR network. We have previously shown that the adenovirus (Ad) E4orf4 protein inhibits DDR signaling, but the mechanisms were not identified. Here, we describe an association of E4orf4 with the DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP-1). E4orf4 reduces phosphorylation of this enzyme and inhibits its activity. PARP-1 inhibition assists E4orf4 in reducing Ad-induced DDR signaling and improves the efficiency of virus replication. Furthermore, the ability of E4orf4, when expressed alone, to accumulate at DNA damage sites and to kill cancer cells is attenuated by chemical inhibition of PARP-1. Our results indicate that the E4orf4–PARP-1 interaction has an important role in Ad replication and in promotion of E4orf4-induced cancer-selective cell death.

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