A Catechol‐Type Resveratrol Analog Manifests Antiangiogenic Action by Constructing an Efficient Catalytic Redox Cycle with Intracellular Copper Ions and NQO1

Abstract

This work provides further evidence that dietary catechols manifest antiangiogenic activity by virtue of their copper-dependent prooxidative instead of antioxidative role, and useful information for designing polyphenol-inspired angiogenesis inhibitors.

Inhibiting NF-κB-Mediated Inflammation by Catechol-Type Diphenylbutadiene via an Intracellular Copper- and Iron-Dependent Pro-Oxidative Role

“…25 Accordingly, we have found that 3,4-DHS works as a copper-dependent pro-oxidant to activate Nrf2 signaling, 22 kills cancer cells selectively, 23 and inhibits angiogenesis. 24 Also, we have verified that elongating the conjugated link of 3,4-DHS is an effective strategy to improve its copper-dependent pro-oxidative ability, as exemplified by the catechol-type diphenylbutadiene (3,4-DHB, Scheme 1). 3,4-DHB has been identified as a more potent tyrosinase (a copper-containing enzyme)-dependent pro-oxidative cytotoxic agent 27 and chemosensitizer 28 against melanoma cells than 3,4-DHS.…”

“…We have previously verified that intracellular copper-mediated oxidation of 3,4-DHS is a critic step for its ability to activate the Nrf2 signal 22 and inhibit angiogenesis. 24 It should be pointed out that intracellular free copper ions are maintained at very low levels, 35 but very low levels of them could efficaciously oxidize catechol-type molecules in a catalytic mode. Alternatively, catechol-type molecules are probably efficient substrates of copper-containing enzymes such as tyrosinase.…”

“…Potential Biological Implications. As part of our continuous efforts in investigating anticancer mechanism details of dietary catechols by employing 3,4-DHS or 3,4-DHB as a model molecule of dietary catechols, [22][23][24]27,28 this work was focused on clarifying that 3,4-DHB is a pro-oxidative anti-inflammatory agent in the LPS-stimulated RAW264.7 cell model. Our data support that depending on intracellular copper and iron ions, 3,4-DHB can be converted from a proelectrophile into the electrophilic o-quinone together with the generation of ROS; these oxidative products mediate its inhibitory activity against NF-κB signaling (including phosphorylation of IKK and IkBα and nuclear translocation of NF-κB) and anti-inflammatory activity (Scheme 2).…”

“…By comparison, the involvement of copper ions is more universal in mediating anticancer activities of 3,4-DHS and 3,4-DHB, including inhibiting inflammation (this work), activating Nrf2 signaling, 22 killing cancer cells selectively, 23,27 sensitizing cancer cells, 28 and controlling angiogenesis. 24 Increased levels of ROS and copper have long been observed in cancer cells compared with normal cells. 38 The biochemical difference is highly needed for maintaining phenotypes of cancer cells such as uncontrolled proliferation, invasion, angiogenesis, and metastasis but makes them more dependent on a "redox adaptation" mechanism to survive and more vulnerable to further ROS generation by pro-oxidants.…”

“…Our above findings support that the pro-oxidative event of 3,4-DHS or 3,4-DHB (as a model molecule of dietary catechols) mediated by copper ions plays an important role in their above anticancer actions. [22][23][24]27,28 Thus, it will be very tempting to further probe whether they inhibit inflammation by virtue of their pro-oxidative role because chronic inflammation is responsible for the development of cancer.…”