<p class="first" id="P1">Although chemotherapy-induced peripheral neuropathy (CIPN)
affects approximately 5-60%
of cancer patients, there are currently no treatments available in part due to the
fact that the underlying causes of CIPN are not well understood. One contributing
factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based
agents such as cisplatin. In support of this hypothesis, overexpression of the base
excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces
DNA damage and protects cultured sensory neurons treated with cisplatin. Here, we
address stimulation of APE1's endonuclease activity through a small molecule, nicorandil,
as a means of mimicking the beneficial effects observed for overexpression of APE1.
Nicorandil was identified through high-throughput screening of small molecule libraries
and found to stimulate APE1 endonuclease activity by increasing catalytic efficiency
approximately 2-fold. This stimulation is primarily due to an increase in k
<sub>cat</sub>. To prevent metabolism of nicorandil, an approved drug in Europe for
the treatment
of angina, cultured sensory neurons were pretreated with nicorandil and daidzin, an
aldehyde dehydrogenase 2 inhibitor, resulting in decreased DNA damage but not altered
transmitter release by cisplatin. This finding suggests that activation of APE1 by
nicorandil in cisplatin-treated cultured sensory neurons does not imbalance the BER
pathway in contrast to overexpression of the kinetically faster R177A APE1. Taken
together, our results suggest that APE1 activators can be used to reduce DNA damage
induced by cisplatin in cultured sensory neurons, although further studies will be
required to fully assess their protective effects.
</p>