A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

Abstract

Abstract. Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling. ER stress caused by overexpression of a fluorescent ER-resident protein, GFP-KDEL, was also attenuated by 16-14 without altering the expression levels of GFP-KDEL. 16-14 also prevented glutathione depletion-induced cell death caused by buthionine sulfoximine (BSO), but not likely via its anti-oxidative activity. Further analysis revealed that 16-14 suppressed increases in intracellular Ca 2+ in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca 2+ homeostasis. [ Supplementary Fig. 1: available only at http://dx.doi.org / 10.1254 / jphs.08136FP]

Synthesis and antimicrobial activities of novel 1H-dibenzo[a,c]carbazoles from dehydroabietic acid

“…Widespread interests of chemists have been attracted to these structures due to their biological activities and potential applications as pharmacological agents [3]. A large number of natural and synthetic carbazole derivatives have been reported to exhibit diverse biological activities such as antimicrobial [4e8], antitumor [9e11], antiviral [12], anti-inflammatory [13], antimalarial [14], antidiarrhoeal [15] and other biological properties such as immunosuppression [16], neuroprotection [17] and pancreatic lipase inhibition [18].…”

Involvement of the Nrf2 Pathway in the Regulation of Pterostilbene-Induced Apoptosis in HeLa Cells via ER Stress

“…All of the specific modulators of ROS and GSH were sufficient to interrupt redox homeostasis in the Pte-treated HeLa cells. Although the direct production of ROS by Pte or the involvement of ROS release from NADPH oxidase (NOX) and mitochondria (Mit) in HeLa cells cannot be ruled out, the data presented here suggest a mechanism for Pte-induced apoptosis: enhanced ROS production in addition to GSH depletion by Pte-induced oxidative stress in the HeLa cells, which resulted in the fine modulation of the intracellular redox homeostasis to facilitate apoptosis (21,49,57,58). In the present study, the Pte-treated HeLa cells showed an induced ER overload response and ER stress, eliciting apoptosis through intracellular redox disorder, caspases activation, and GRP78 and CHOP expression.…”

Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death

“…11 Further, the carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole], which was able to maintain PC12 cellular Ca 2+ homeostasis by compensation of the thapsigargin-induced [Ca 2+ ] ER release, also attenuated the UPR after ER stress stimuli. 12 Therefore, the modulating effects of CyPPA pretreatment on the different transcription factors linked to the UPR may also be attributed to the stabilization of intracellular Ca 2+ homeostasis. Surprisingly, the combinatory treatment of brefeldin A and CyPPA had synergistic effects on CHOP protein levels (Figure 3c).…”

“…10 Additionally, pharmacological applications that interfere with alterations of the intracellular calcium homeostasis have a protective potential against ER stress-induced cell death. 11,12 Several ER-located potassium channels are supposed to be important for [Ca 2+ ] ER uptake and release by maintenance of the countercurrent required for electroneutrality. 13 For instance, small-conductance calcium-activated potassium (SK) channels have recently been detected in the sarco-/ endoplasmic reticulum of cardiomyocytes and neurons, respectively, where they may regulate [Ca 2+ ] ER uptake.…”