NQO1 Bioactivatable Drugs Enhance Radiation Responses View Full Text


Ontology type: schema:Chapter     


Chapter Info

DATE

2016-10-21

AUTHORS

Erik A. Bey , Julia C. Meade , Molly A. Silvers , Edward A. Motea , Praveen L. Patidar , Rolf Brekken , Stanislaw Deja , Matthew E. Merritt , Jessica A. Kilgore , Yuliang Liu , Xiumei Huang , Longshan Li , John Yordy , Noelle S. Williams , Jinming Gao , David A. Boothman

ABSTRACT

Inhibitors of cancer-specific pathways can selectively kill off tumor cells. However, heterogeneity of neoplastic tissue often allows other cancer cells to repopulate the tissue area, leading to regeneration of resistant disease. β-Lapachone is a novel bioactivatable drug that relies specifically on tumor-directed upregulated levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) to kill most solid cancers, such as 90 % of pancreatic and non-small cell lung, 60 % of breast, colon, and prostate, as well as 50 % of head and neck cancers. Once β-lapachone is bioactivated by the NQO1 enzyme, massive levels of hydrogen peroxide are produced that, in turn, damage the DNA of cancer cells, while associated normal tissues, which lack NQO1, are protected by high levels of catalase. If tumors are irradiated prior to applying β-lapachone, the drug (clinical form, ARQ761) can work in combination with the vast spectrum of DNA lesions created by ionizing radiation, particularly DNA base lesions, single and double strand breaks (SSBs and DSBs), in addition to the massive hydrogen peroxide-based lesions created by β-lapachone, to cause tumor-dependent poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Once tumor-selective PARP hyperactivation is induced in cancer cells, they die due to low concomitant catalase levels. In contrast, associated normal tissue, as well as other normal tissue, lack elevated levels of NQO1 and have high catalase levels. Cancer cell death ultimately occurs by NAD+-depletion, where resistance to NQO1 bioactivatable drugs has not been noted to date. Current studies are focused on pancreatic and non-small cell lung cancers, as NQO1 is elevated in nearly all of these cancers. More... »

PAGES

225-252

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/978-3-319-45594-5_10

DOI

http://dx.doi.org/10.1007/978-3-319-45594-5_10

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1052111091


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22 area
23 base lesions
24 bioactivatable drug
25 breaks
26 breast
27 cancer
28 cancer cell death
29 cancer cells
30 cancer-specific pathways
31 catalase
32 catalase levels
33 cell death
34 cell lung
35 cell lung cancer
36 cells
37 colon
38 combination
39 concomitant catalase levels
40 contrast
41 current study
42 date
43 death
44 disease
45 double strand breaks
46 drugs
47 elevated levels
48 enzyme
49 head
50 heterogeneity
51 high catalase levels
52 high levels
53 hydrogen peroxide
54 hydrogen peroxide-based lesions
55 hyperactivation
56 inhibitors
57 lack elevated levels
58 lapachone
59 lesions
60 levels
61 low concomitant catalase levels
62 lung
63 lung cancer
64 massive hydrogen peroxide-based lesions
65 massive levels
66 most solid cancers
67 neck cancer
68 neoplastic tissues
69 non-small cell lung
70 non-small cell lung cancer
71 normal tissues
72 novel bioactivatable drug
73 oxidoreductase 1
74 pathway
75 peroxide
76 peroxide-based lesions
77 polymerase 1 (PARP1) hyperactivation
78 prostate
79 quinone oxidoreductase 1
80 radiation
81 radiation response
82 regeneration
83 resistance
84 resistant disease
85 response
86 solid cancers
87 spectra
88 strand breaks
89 study
90 tissue
91 tissue area
92 tumor cells
93 tumor-directed upregulated levels
94 tumor-selective PARP hyperactivation
95 tumors
96 turn
97 upregulated levels
98 vast spectrum
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