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Journal of Biomedical Research | Volume: 29
November 19-20, 2018 | Paris, France
Molecular Biology, Tissue Science and Regenerative Medicine
International Conference on
Joint Event
&
4th World Heart Congress
Leveraging NQO1 bioactivatable drugs for tumor-selective PARP inhibitor synergy for pancreas, breast
and nonsmall cell lung cancers
David A Boothman
Indiana University, USA
Therapeutic drugs that block DNA repair, including poly
(ADP-ribose) polymerase (PARP) inhibitors, fail due to
lack of tumor-selectivity. When PARP inhibitors and NQO1
bioactivatable drugs are combined, synergistic antitumor
activity results from sustained NAD(P)H levels that refuel
NQO1-dependent futile redox drug recycling. Significant
oxygen consumption rate/reactive oxygen species cause
dramatic (DNA) lesion increases that are not repaired due to
PARP inhibition. InNQO1+cancers, suchasnon-small cell lung,
pancreatic and breast, the cell death mechanism switches
from PARP1 hyperactivation-mediated programmed necrosis
with NQO1 bioactivatable drug monotherapy to synergistic
tumor-selective, caspase-dependent apoptosis with PARP
inhibitors and NQO1 bioactivatable drugs. Complete
metabolic profiling of cells containing or lacking NQO1 and
treated with PARP inhibitor Rucaparib along with the NQO1
bioactivatable drug, ß-lapachone, demonstrated dramatic
shifts from suppression of glycolytic and KREB’s cycle with
NQO1 bioactivatable drugs alone to apoptotic activation
with PARP inhibitors along with the NQO1 bioactivatable
drug. Synergistic antitumor efficacy and prolonged survival
were noted in human orthotopic pancreatic and non-small
cell lung xenograft models, expanding use and efficacy of
PARP inhibitors for human cancer therapy. Cell death was
found independent of oncogenic driver mutations or over-
expressed oncogenes or loss of tumor suppressors. This
work was supported by NIH/NCI R01 grants, R01 CA102792-
16 and R01 CA221158-01 to DAB.
e:
Molecular Biology & Heart Congress 2018, Volume 29
DOI: 10.4066/biomedicalresearch-C8-023