NAD(P)H:Quinone Oxidoreductase 1 (NQO1) as a Therapeutic and Diagnostic Target in Cancer

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron reductase responsible for detoxification of quinones and also bioactivation of certain quinones. It is abnormally overexpressed in many tumors and intimately linked with multiple carcinogenic processes. NQO1 is considered to be a cancer-specific target for therapy but currently available NQO1 inhibitors have not yet led to chemotherapeutic success. Utilization of NOQ1's ability to bioactivate chemotherapeutic quinones, however, has emerged as a promising selective anticancer therapy. On the basis of the different levels of NQO1 between cancer and normal cells, the catalytic property of NQO1 has recently been exploited to develop effective probes for cancer detection. This article summarizes the most significant advances concerning the discovery and development of NQO1 inhibitors, NQO1-directed chemotherapeutic quinones, and NQO1-activated optical probes, along with the prospects and potential obstacles in this research area.

An Activatable Photosensitizer Targeting Human NAD(P)H: Quinone Oxidoreductase 1

“…[13][14][15][16][17][18][19][20][21][22][23][24][25] Severalg roupsh avea lso developed hNQO1-bioactivated anticancera gents(e.g.,p rodrugs) to enhancet he cancers electivity of DNA alkylators or other chemotherapeutic agents. [9,[26][27][28][29][30] Lastly,t heranostic prodrugs providingb oth real-time hNQO1 activity monitoring and anticancer drug release in as ingle molecule have also been reported. [31,32] However,d espite the diverse seto fp robesc urrently exploitingh NQO1, to date, there are no reportso fa nh NQO1targeted optical therapeutic that can be used for PDT.…”

“…It has primary roles in detoxification, antioxidation and stabilization of p53 against proteasomal degradation . In many cancers, hNQO1 can be significantly overexpressed relative to its healthy tissue counterpart . For example, there is a 10‐ to 100‐fold increase in hNQO1 levels in pancreatic cancer and its activity has been shown to be up to 90 times higher in lung cancers and at least 6 times higher in breast cancer .…”

“…For example, an array of fluorescent chemosensors have been developed to differentiate cancer cells from healthy cells, and in some instances identify metastases in animal models . Several groups have also developed hNQO1‐bioactivated anticancer agents (e.g., prodrugs) to enhance the cancer selectivity of DNA alkylators or other chemotherapeutic agents . Lastly, theranostic prodrugs providing both real‐time hNQO1 activity monitoring and anticancer drug release in a single molecule have also been reported .…”

“…[7] In many cancers, hNQO1c an be significantly overexpressed relative to its healthy tissue counterpart. [8,9] For example, there is a1 0-to 100-fold increase in hNQO1l evels in pancreatic cancer [9][10][11] and its activity has been shownt ob eu p to 90 times higher in lung cancers and at least 6t imes higher in breast cancer. [12] Overexpression of hNQO1 has also been found at levels5 -200 times higheri ns tomach, colon,h ead and neckc ancers, and cholangiocarcinoma, compared to their normal tissues.…”

“…[12] Overexpression of hNQO1 has also been found at levels5 -200 times higheri ns tomach, colon,h ead and neckc ancers, and cholangiocarcinoma, compared to their normal tissues. [9] Despite its high expression levels in manyc ancers, and the availability of as mall molecule substrate (i.e., quinones), no activatable PDT probesf or hNQO1 exists to date. Rather,i ts high level has been mainlye xploited for diagnostics and alternative therapeutic applications.F or example, an array of fluorescent chemosensors have been developed to differentiate cancer cells from healthy cells, and in some instances identify metastases in animal models.…”