Valproate markedly boosts ability of niraparib to kill tumor cells

Naveed Saleh, MD, MS, for MDLinx | July 27, 2018

Adding sodium valproate, a histone deacetylase (HDAC) inhibitor, potentiates the anti-tumor activity of niraparib, according to a recent study published in Cancer & Biology Therapy. Niraparib is a poly-ADP ribose polymerase 1 (PARP1) and PARP2 inhibitor, which is approved for the treatment of all types of ovarian cancer—regardless of BRCA status.

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AR42 and sodium valproate, both HDAC inhibitors, synergistically heightened the anti-tumor effects of niraparib against mammary and ovarian cancer cells.

“As we discovered that niraparib could modestly enhance autophagosome formation, we wished to determine whether HDAC inhibitors, particularly the inexpensive inhibitor sodium valproate, would interact with this PARP1/2 inhibitor in a greater than additive fashion to cause autophagosome formation and to promote tumor cell death,” wrote the authors, led by Laurence Booth, PhD, Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA.

The researchers have previously shown that HDAC inhibitors potently mediate increased autophagosome levels when added to a variety of agents that cause DNA damage. PARP1 moderates DNA damage repair. In tumor cells low in PARP1, single- and double-stranded DNA damage piles up because these deficient cells are less able to trigger the DNA damage sensing kinase ATM.

Although the inhibition of PARP1 via PARP1 inhibitors yields DNA damage, this inhibition quickly activates ATM. In the current study, the researchers used cell studies to verify one form of niraparib toxicity stemming from this DNA damage and ATM activation (via AMPK). Of note, niraparib lethality is a complicated aponecrotic iteration of tumor cell death.

Specifically, ATM activation phosphorylates TSC2 and Raptor resulting in mTOR inactivation. This mechanism amplifies the phosphorylation of ULK-1 S317. One substrate of mTOR, which at this point has been inactivated by ATM activation, is ULK-1 S757. As expected, niraparib decreases ULK-1 S757 phosphorylation.

These phosphorylation changes in ULK-1 metabolism are linked to kinase activation, which was evidenced by the augmented phosphorylation of ATG13 S318, a ULK-1 direct substrate. Finally, phosphorylation of ATG13 S318 supports autophagosome formation. On the basis of knock down data and viability assays, the investigators noted that this autophagy drove the death of tumor cells. Of interest, the researchers observed that over time, levels of autophagosomes reduced and autolysosomes increased thus indicating autophagic flux.

“Studies from ourselves and others have demonstrated that HDAC inhibitors can enhance autophagosome formation, promote endoplasmic reticulum stress signaling and cause expression and activation of death receptor pathways,” the authors wrote.

In the current study, the team found that AR42 and sodium valproate, both HDAC inhibitors, synergistically heightened the anti-tumor effects of niraparib vs mammary and ovarian cancer cells by increasing the activation of ATM-AMPK-ULK1-autophagy and CD95-FADD-caspase 8 pathways. Ultimately, combining niraparib and valproate resulted in increased levels of autophagosome vis-à-vis autolysosome formation.

The researchers found that when used alone, niraparib impeded tumor growth but failed to significantly budge tumor control rate in mouse models. They found that post-therapy in tumor cells treated with niraparib, these cells grew faster than those in the vehicle control. In tumor-harboring mouse models previously treated with niraparib, tumors changed to secrete higher levels of human-growth factors and cytokines.

When used alone or combined with valproate, niraparib changed the expression of proteins that alter tumor cell immunogenicity. Although immunotherapy leveraging checkpoint inhibitory antibodies is approved for the treatment of various other cancers, this approach is not currently approved for the treatment of mammary or ovarian cancers.

“Our two-agent combination of [niraparib + valproate] has the potential to both kill tumor cells but also to opsonize them to the anti-tumor effects of checkpoint inhibitory antibodies,” the authors concluded. “Further animal studies, to demonstrate the in vivo interaction between niraparib and valproate, and to determine whether [niraparib + valproate] opsonizes tumor cells to checkpoint inhibitory immunotherapy antibodies will be performed in future studies.”

This study was funded in part by Massey Cancer Center and the Universal Inc. Chair in Signal Transduction Research.

To read more about this study, click here

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