Biology Reference
In-Depth Information
FIGURE 3.3
Cartoon of APE1 protein showing that the redox portion resides in the N-terminus (C65 and C93) and the repair function is
located in the C-terminus (H309). Published inhibitors of each function are listed below as well as the effects of APE1 siRNA on tumor cell
viability and function. It is important to note that these effects have mainly been demonstrated in tumor cells. Inhibition of APE1 could have
different effects based on the cell-type, i.e. endothelial cells or tumor-associated macrophages.
the BER pathway, may have clinical implications and
benefit in cancer treatment.
2,188
Proteins being considered as viable targets for cancer
treatment within the BER pathway include: FEN1, Pol
b
,
APE1 (
Figure 3.3
), and PARP1. We will briefly discuss
FEN1 and Pol
b
and dedicate the majority of our discus-
sion to APE1 and PARP1 inhibitors as these are further
along in preclinical and clinical development. Studies
in colon cancer cells demonstrate that small molecule
inhibitor,
NSC
-281680, inhibits FEN1 endonuclease
activity and potentiates the cytotoxicity of TMZ regard-
less of the MMR status of the cells.
189
Pol
b
, the poly-
merase in both long- and short-patch BER, has
associated lyase activity that is often rate-limiting in
BER. Due to this, its role in resistance, and overexpres-
sion in tumor cells, Pol
b
is a potential target for poten-
tiation of tumor cells to DNA damaging agents. Hecht's
group identified four Pol
b
inhibitors: oleanolic acid,
edgeworin, betulinic acid, and stigmasterol, character-
ized their mechanism of action, and demonstrated that
they could potentiate the cytotoxcity of bleomycin.
190
A recent virtual screening process called relaxed
complex scheme revealed novel and more potent Pol
b
lyase activity inhibitors
191
compared to pamoic acid,
one of the first characterized Pol
b
inhibitors which
inhibited both the lyase and polymerase functions.
192
Specific inhibition of the lyase activity may be more
desirable than the polymerase activity because it is
often the rate-limiting step in BER and because it is
difficult to develop a very specific inhibitor to the poly-
merase domain that would not also inhibit polymerases
involved in DNA replication. Consistent with the
synthetic lethality approach involving PARP1 and
BRCA proteins, cancer cells with defects in MMR
protein, MSH2, were extremely sensitive to siRNA to
Pol
b
as well as Pol
b
inhibitor, masticadienonic
acid.
193
Interestingly, cancer cells deficient in MMR
protein, MLH1 were sensitive to inhibition of DNA pol
g
and not by Pol
b
. These experiments nicely illustrate
the importance of overlapping DNA repair pathways
and the potential to exploit the inherent deficiencies in
tumors as we learn more about the biology of the tumor.
