1,4-Diselenophene-1,4-diketone Triggers Caspase-Dependent Apoptosis in Human Melanoma A375 Cells through Induction of Mitochondrial Dysfunction

Abstract

Epidemiological, preclinical and clinical studies have supported the role of selenocompounds as potential cancer chemopreventive and chemotherapeutic agents. In this study, a novel selenophene-based compound, 1,4-diselenophene-1,4-diketone (DSeD), has been synthesized by Double Friedel-Crafts reaction and identified as a potent antiproliferative agent against a panel of six human caner cell lines. Despite this potency, DSeD was relatively nontoxic toward human normal cells, HS68 fibroblasts and HK-2 kidney cells. These results suggest that DSeD possesses great selectivity between cancer and normal cells. Induction of apoptosis in human melanoma A375 cells by DSeD was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Activation of caspase-9 and depletion of mitochondrial membrane potential indicated the initiation of the mitochondria-mediated apoptosis pathway. Pretreatment of cells with general caspase inhibitor z-VAD-fmk and caspase-9 inhibitor z-LEHD-fmk significantly suppressed the cell apoptosis, demonstrating the important roles of caspase and mitochondria in DSeD-induced apoptotic cell death. Furthermore, DSeD-induced apoptosis was found independent of reactive oxygen species generation. Taken together, our results suggest that DSeD induces caspase-dependent apoptosis in A375 cells through activation of mitochondria-mediated apoptosis pathway.

Inhibition of melanoma development in the Nras(Q61K)::Ink4a−/− mouse model by the small molecule BI‐69A11

“…Recent studies point to the role of altered lipid metabolism in cancer progression (Santos and Schulze, 2012). Likewise, mitochondrial dysfunction, the downregulation of which was associated with resistance to BI-69A11, is associated with cell death (Luo et al, 2011). Notably, the increase in COP9 signalosome and…”

“…Recent studies point to the role of altered lipid metabolism in cancer progression (Santos and Schulze, ). Likewise, mitochondrial dysfunction, the downregulation of which was associated with resistance to BI‐69A11, is associated with cell death (Luo et al., ). Notably, the increase in COP9 signalosome and ubiquitination/glutathione metabolism pathways has been associated with tumorigenesis (Luo et al., ; Singh et al., ), suggesting that their downregulation in the BI‐69A11‐treated tumors could represent tumor‐suppressive effects, albeit, insufficient to suppress the tumors.…”

A Novel Selenadiazole Derivative Induces Apoptosis in Human Glioma Cells by Dephosphorylation of AKT

“…2A), as reflected in the sub-G1 populations (11.5-81.4%). These results suggest that BSBD, like many other selenium compounds, 7,18,19) induces apoptosis in SWO-38 cells. These findings were confirmed by 4′,6-diami- dino-2-phenylindole (DAPI) staining.…”

“…Moreover, BSBD exhibited minimal cytotoxicity towards the normal cell lines HK-2, LO-2, MCF-10A and HOPC-5, which represents a significant improvement in selectivity compared with previous reports. 18,19) As shown in Fig. 1B, BSBD treatment led to a dose-dependent inhibition of cell growth: 12-88% inhibition after 48 h of treatment with BSBD (4-120 µM).…”

“…18) For instance, 1,2,5-selenadiazolo- [3,4-d]pyrimidine-5,7-(4H,6H)-dione was identified as a potent antiproliferative agent when tested in several human cell lines, including MCF-7 breast carcinoma, HepG2 hepatoma and A375 melanoma cells. 18) In addition, 1,4-diselenophene-1,4-diketone was shown to induce caspase-dependent mitochondrial apoptosis in A375 human melanoma cells, 19) and 1,2-(5,5′-dimethoxybis(1,2-benzisoselenazol-3(2H)-one))-ethane was shown to inactivate thioredoxin reductase (TrxR) in several cancer cell lines. 20) However, the selectivity of these compounds is poor, and their mechanisms of action have not been well clarified.…”