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Cancer Biol Ther. 2018;19(9):797-808. doi: 10.1080/15384047.2018.1472190. Epub 2018 Aug 1.

Valproate augments Niraparib killing of tumor cells.

Author information

1
a Departments of Biochemistry and Molecular Biology , Virginia Commonwealth University , Richmond , VA , USA.
2
b Medicine , Virginia Commonwealth University , Richmond , VA , USA.

Abstract

PARP1 inhibitors are approved therapeutic agents in ovarian carcinomas, and have clinical activity in some breast cancers. As a single agent, niraparib killed ovarian and mammary tumor cells via an ATM-AMPK-ULK1 pathway which resulted in mTOR inactivation and the formation of autophagosomes, temporally followed by autolysosome formation. In parallel, niraparib activated a CD95-FADD-caspase 8 pathway, and collectively these signals caused tumor cell death that was suppressed by knock down of Beclin1, ATG5, CD95, FADD or AIF; or by expression of c-FLIP-s, BCL-XL or dominant negative caspase 9. The HDAC inhibitors AR42 and sodium valproate enhanced niraparib lethality in a greater than additive fashion. HDAC inhibitors enhanced niraparib lethality by increasing activation of the ATM-AMPK-ULK1-autophagy and CD95-FADD-caspase 8 pathways. Knock down of eIF2α, ATM, AMPKα, ULK1, Beclin1 or ATG5 reduced tumor cell killing by the niraparib plus HDAC inhibitor combination. Blockade of either caspase 9 function or that of cathepsin B partially prevented cell death. As a single agent niraparib delayed tumor growth, but did not significantly alter the tumor control rate. Tumors previously exposed to niraparib had activated the ERK1/2 and AKT-mTOR pathways that correlated with increased plasma levels of IL-8, MIF, EGF, uPA and IL-12. Collectively our findings argue that the addition of HDAC inhibitors to niraparib enhances the anti-cancer activity of the PARP1 inhibitor niraparib.

KEYWORDS:

DNA damage; HDAC; autophagy

PMID:
29923797
PMCID:
PMC6154859
[Available on 2019-08-01]
DOI:
10.1080/15384047.2018.1472190

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