GdCl3 Induced Hep G2 Cell Death through Mitochondrial and External Death Pathways without Significant Elevation of ROS Generation

Abstract

Gadolinium (Gd) compounds have important applications as MRI contrast and potential anticancer agents. The present study investigated the mechanisms of the proapoptotic effect of gadolinium chloride (GdCl(3)) on hepatoblastoma cell line (Hep G2) tumor cells. The experimental results indicated that GdCl(3) induced apoptosis of Hep G2 at high concentration and with long time incubation; however, unlike the actions on normal cell lines, GdCl(3) did not cause any oxidative stress on tumor cells. Cytochrome c (Cyt c) and apoptosis inducing factor release, Bax translocation, collapse of mitochondria membrane potential, caspase 3 and 8 activation, and Bid cleavage were observed along with a sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK). Addition of ERK and JNK inhibitor attenuated the effect of GdCl(3) induced apoptosis and Cyt c release. All the results suggested a novel mechanism that GdCl(3) induced Hep G2 cell death through intrinsic and external death pathways without significant elevation of reactive oxygen species generation. The present work provided new insight to understand the mechanisms of the biological effects of GdCl(3) and implications for the development of anticancer Gd agents.

Caspase‑dependent apoptotic death by gadolinium chloride (GdCl3) via reactive oxygen species production and MAPK signaling in rat C6 glioma cells

“…These results suggested that GdCl 3 can accumulate and be uptaken by tumors in the brain through favorable permeability of the BTB and BBB. In addition, Gd compounds possess diverse anticancer activities (8,11). Previous studies have shown that after treatment with a relatively low concentration of GdCl 3 , cell cycle progression and cell growth were promoted, whereas human hepatoma HepG2 and osteosarcoma U-2 OS cells exposed to high concentrations of GdCl 3 exhibited apoptosis and suppressed cell proliferation (8,11).…”

“…In addition, Gd compounds possess diverse anticancer activities (8,11). Previous studies have shown that after treatment with a relatively low concentration of GdCl 3 , cell cycle progression and cell growth were promoted, whereas human hepatoma HepG2 and osteosarcoma U-2 OS cells exposed to high concentrations of GdCl 3 exhibited apoptosis and suppressed cell proliferation (8,11). It is suggested that GdCl 3 -induced apoptosis is specific to HepG2 cells (11), U-2 OS cells (8) and rat C6 glioma cells.…”

“…Lanthanide (Ln) ions have the chemical properties of both a high coordination number and a charge density, and they have been previously applied in agriculture and medicine (7)(8)(9)(10)(11)(12). Gadolinium (Gd), a member of the Ln series, exerts a magneto-caloric effect (8).…”

“…Gadolinium (Gd), a member of the Ln series, exerts a magneto-caloric effect (8). Gd compounds including Gd chloride (GdCl 3 ) have been applied as magnetic resonance imaging (MRI) contrast agents and may be promising anticancer drugs (8)(9)(10)(11)(12). GdCl 3 is widely used for in-activating tumor-associated macrophages (9,13).…”

“…GdCl 3 is widely used for in-activating tumor-associated macrophages (9,13). In addition, GdCl 3 was found to inhibit cell proliferation and induce apoptosis in human hepatoma HepG2 cells through a mitochondria-dependent pathway (11). Recently, we reported that GdCl 3 triggers apoptotic death in human osteosarcoma U-2 OS cells through the death receptor, mitochondria-dependent and ER stress pathways (8).…”