A new copper ionophore DPMQ protects cells against ultraviolet B irradiation by inhibiting the TRPV1 channel. Issue 12 (26th June 2018)

• Record Type: Journal Article
• Authors: Huang, Kuo‐Feng; Ma, Kuo‐Hsing; Hung, Yu‐Chien; Lo, Liang‐Chuan; Lin, Kuo‐Chen; Liu, Pei‐Shan; Hu, Ming‐Kuan; Chueh, Sheau‐Huei
• Is Part Of: Journal of cellular physiology. Volume 233:Issue 12(2018:Dec.)
• Page Start: 9594
• Page End: 9610
• Publication Date: 2018-06-26
• Subjects: cytosolic calcium concentration -- Nrf2 -- reactive oxygen species -- TRPV1 channel -- ultraviolet B irradiation.; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.26861
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : Copper is more likely than iron to generate reactive oxygen species (ROS) in a redox reaction due to its higher electrochemical reactivity. This study examined the effect of a newly synthesized Cu 2+ binding compound, ( E )‐2‐(4‐(dimethylamino)phenylimino)methyl)quinolin‐8‐ol (DPMQ), on ultraviolet B (UVB) irradiation–induced cytotoxicity in human dermal fibroblasts. DPMQ induced Cu 2+ influx as effectively as disulfiram, a Cu 2+ ionophore anticancer drug. However, disulfiram induced ROS generation, mitochondrial dysfunction, and apoptosis in fibroblasts in a Cu 2+ ‐dependent manner, whereas DPMQ was not only nontoxic, but protected cells against UVB irradiation–induced apoptosis in a Cu 2+ ‐independent manner. UVB irradiation induced a Ca 2+ ‐dependent increase in ROS generation, a decrease in Nrf2 levels, and activation of the mitochondrial apoptotic pathway, and these effects were prevented by DPMQ, which also increased Nrf2 nuclear translocation in a Cu 2+ ‐independent manner. UVB irradiation activated 12‐lipoxygenase and 12‐hydroxyeicosatetraenoic acid (12‐HETE), a product of 12‐lipoxygenase, activated the TRPV1 channel. DMPQ did not act as a Ca 2+ chelator, but inhibited the cytosolic Ca 2+ increase induced by 12‐HETE or capsaicin, but not that induced by bradykinin or ATP. Blockade of Ca 2+ influx by pharmacological inhibition or silencing of the TRPV1 channel or chelation of cytosolic Ca 2+ inhibited the UVB irradiation–induced Nrf2 reduction, ROS generation, mitochondrial dysfunction, and apoptosis. Taken together, our results suggest that Ca 2+ influx via the TRPV1 channel is responsible for UVB irradiation–induced cytotoxicity and that DPMQ protects cells against UVB irradiation by inhibiting the TRPV1 channel and stabilizing Nrf2, and could thus be a potentially useful compound for the treatment of free radical‐induced diseases. Abstract : Treatment of cells with ultraviolet B (UVB) irradiation results in increased reactive oxygen species (ROS) generation and decreased Nrf2 levels by a mechanism involving lipoxygenase stimulation and TRPV1 channel activation. Increased ROS results in mitochondrial dysfunction and apoptosis. DPMQ inhibits the TRPV1 channel and scavenges ROS, and hence protects cells against UVB irradiation–induced cytotoxicity, whereas disulfiram induces copper influx and increases ROS generation, and therefore causes apoptosis.