Paper Spotlight: Combination of HDACi, PARPi and Chemotherapeutic Agents Treat Hematologic Cancer

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Oncotarget

Oncotarget published this trending research paper in Volume 13, entitled, "HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs" by researchers from the Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada. DOI - https://doi.org/10.18632/oncotarget.28278 Correspondence to - Benigno C. Valdez - bvaldez@mdanderson.org Abstract The therapeutic efficacy of histone deacetylase inhibitors (HDACi) for hematologic malignancies and solid tumors is attributed to their ability to remodel chromatin, normalize dysregulated gene expression, and inhibit repair of damaged DNA. Studies on the interactions of HDACi with PARP inhibitors in hematologic cancers are limited, especially when combined with chemotherapeutic agents. Exposure of hematologic cancer cell lines and patient-derived cell samples to various HDACi resulted in a significant caspase-independent inhibition of protein PARylation, mainly catalyzed by PARP1. HDACi affected the expression of PARP1 at the transcription and/or post-translation levels in a cell line-dependent manner. HDACi-mediated inhibition of PARylation correlated with decreased levels and phosphorylation of major proteins involved in DNA repair. Combination of HDAC and PARP1 inhibitors provided synergistic cytotoxicity, which was further enhanced when combined with a chemotherapeutic regimen containing gemcitabine, busulfan and melphalan as observed in lymphoma cell lines. Our results indicate that the anti-tumor efficacy of HDACi is partly due to down-regulation of PARylation, which negatively affects the status of DNA repair proteins. This repair inhibition, combined with the high levels of oxidative and DNA replication stress characteristic of cancer cells, could have conferred these hematologic cancer cells not only with a high sensitivity to HDACi but also with a heightened dependence on PARP and therefore with extreme sensitivity to combined HDACi/PARPi treatment and, by extension, to their combination with conventional DNA-damaging chemotherapeutic agents. The observed synergism of these drugs could have a major significance in improving treatment of these cancers. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28278 Keywords - poly(ADP-ribosyl)ation, HDAC inhibitors, PARP inhibitors, chemotherapy, hematologic malignancy About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957