Table 4 Possible combinations of valproic acid (VPA) with other therapeutic agents: current experimental evidence

Curcumin

Curcumin is a natural anticancer agent that affects the expression of NF-κB, Bcl-2 and Bax in leukemic cells. The combination with VPA causes upregulation of Bax with proliferation arrest, sub-G1 DNA accumulation and cell death in the HL-60 AML cell line. The effect is dependent on p38 activation.

Chen et al., 2010 [100]

Folate receptor beta

The folate receptor beta mediates antiproliferative effects in AML cells and VPA upregulates the expression of this receptor. VPA and ATRA, combined with targeting of this receptor, may therefore have additive or synergistic antileukemic effects.

Qi and Ratnam, 2006 [105]

HSP90 inhibition

Co-treatment of the AML1/ETO-expressing Kasumi-1 cell line with VPA and the HSP90 inhibitor 17-AAG causes a synergistic inhibition of downstream signaling of mutated c-KIT.

Yu et al., 2011 [108]

Hydralazine

Hydralazine is a nontoxic agent with DNA MTase-inhibiting effects. A clinical study suggested that the combination of hydralazine and VPA was a nontoxic treatment with an antileukemic effect in vivo. The effect has not been compared with VPA in combination with decitabine or 5-AZA.

Candelaria et al., 2011 [99]

mTOR inhibition

Studies in AML cell lines show no additive proapoptotic effects, but only a limited number of cell lines were examined. However, in other experimental models of Flt3-ITD-transformed cells, VPA and mTOR inhibitors had synergistic proapoptotic effects.

Cai et al., 2006 [98]; Ryningen et al., 2012 [106]

NF-κB inhibition

Experimental studies suggest that the antileukemic effect of DNA MTase and HDAC inhibition is not only caused by epigenetic mechanisms, but also by additional and independent inhibition of NF-κB. Specific NF-κB inhibitors are now being developed and the antileukemic effects of proteasome inhibitors are also most likely caused by NF-κB inhibition.

Fabre et al., 2008 [101]

p53 agonism, nutlin

The p53 agonist nutlin was combined with VPA, and the two drugs caused a synergistic induction of p53-dependent apoptosis in AML cell lines and primary AML cells. This synergism was also demonstrated in xenograft models of human AML.

McCormack et al., 2012 [103]

Proteasome inhibitors, including bortezomib

This combination has an antiproliferative effect with cell cycle arrest of AML cell lines. Apoptosis is induced through caspase activation, and inhibition of cyclin D and telomerase is induced. The two drugs have synergistic effects. This synergism is also seen for other proteasome inhibitors, and, at least in certain experiments, the antileukemic effect is stronger for the proteasome inhibitors NPI-0051 and PR-171 than for bortezomib.

Fuchs et al., 2009 [102]; Nie et al., 2012 [104]; Wang et al., 2011 [107]

sTRAIL

When VPA was combined with an anti-CD33 single chain fragment linked to sTRAIL, the two agents had synergistic effects on apoptosis induction in primary human AML cells.

ten Cate et al., 2009 [109]