Panobinostat Synergizes with Chemotherapeutic Agents and Improves Efficacy of Standard-of-Care Chemotherapy Combinations in Ewing Sarcoma Cells.

Autor:	Smith, Kaitlyn H., Trovillion, Erin M., Sholler, Chloe, Gandra, Divya, McKinney, Kimberly Q., Mulama, David, Dykema, Karl J., Nagulapally, Abhinav B., Oesterheld, Javier, Saulnier Sholler, Giselle L.
Předmět:	THERAPEUTIC use of antineoplastic agents RESEARCH funding TUMORS in children ANTINEOPLASTIC agents CELL cycle CANCER cell culture CANCER chemotherapy RNA BIOINFORMATICS GENE expression CELL lines ETOPOSIDE DRUG efficacy DOXORUBICIN DNA damage EWING'S sarcoma CELL survival DRUG synergism HISTONE deacetylase PHARMACODYNAMICS
Zdroj:	Cancers; Nov2024, Vol. 16 Issue 21, p3565, 18p
Abstrakt:	Simple Summary: There has been little improvement in Ewing sarcoma survival rates over the past several decades and new therapeutic options are desperately needed. Histone deacetylases (HDACs) are known to play a role in cancer development and progression. We show that HDAC2 is overexpressed in Ewing sarcoma cells and that an HDAC inhibitor, Panobinostat, is cytotoxic to Ewing sarcoma cells both alone and when combined with standard of care. Mechanistically, we show that Panobinostat increases the DNA damage caused by standard of care leading to the death of the Ewing sarcoma cells. We believe that HDAC inhibition combined with standard-of-care chemotherapeutics may be an effective treatment option for Ewing sarcoma patients. Background: The survival rate of patients with Ewing sarcoma (EWS) has seen very little improvement over the past several decades and remains dismal for those with recurrent or metastatic disease. HDAC2, ALK, JAK1, and CDK4 were identified as potential targets using RNA sequencing performed on EWS patient tumors with the bioinformatic analysis of gene expression. Methods/Results: The pan-HDAC inhibitor Panobinostat was cytotoxic to all the Ewing sarcoma cell lines tested. Mechanistically, Panobinostat decreases the expression of proteins involved in the cell cycle, including Cyclin D1 and phospho-Rb, and DNA damage repair, including CHK1. Further, Panobinostat induces a G1 cell cycle arrest. The combination of Panobinostat with Doxorubicin or Etoposide, both of which are used as standard of care in upfront treatment, leads to a synergistic effect in EWS cells. The combination of Panobinostat and Doxorubicin induces an accumulation of DNA damage, a decrease in the expression of DNA damage repair proteins CHK1 and CHK2, and an increase in caspase 3 cleavage. The addition of Panobinostat to standard-of-care chemotherapy combinations significantly reduces cell viability compared to that of chemotherapy alone. Conclusions: Overall, our data indicate that HDAC2 is overexpressed in many EWS tumor samples and HDAC inhibition is effective in targeting EWS cells, alone and in combination with standard-of-care chemotherapy agents. This work suggests that the addition of an HDAC inhibitor to upfront treatment may improve response. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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