Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

Abstract

Gadolinium (Gd) compounds are important as magnetic resonance imaging (MRI) contrast agents, and are potential anticancer agents. However, no report has shown the effect of gadolinium chloride (GdCl3) on osteosarcoma in vitro. The present study investigated the apoptotic mechanism of GdCl3 on human osteosarcoma U-2 OS cells. Our results indicated that GdCl3 significantly reduced cell viability of U-2 OS cells in a concentration-dependent manner. GdCl3 led to apoptotic cell shrinkage and DNA fragmentation in U-2 OS cells as revealed by morphologic changes and TUNEL staining. Colorimetric assay analyses also showed that activities of caspase-3, caspase-8, caspase-9 and caspase-4 occurred in GdCl3-treated U-2 OS cells. Pretreatment of cells with pan-caspase inhibitor (Z-VAD-FMK) and specific inhibitors of caspase-3/-8/-9 significantly reduced cell death caused by GdCl3. The increase of cytoplasmic Ca2+ level, ROS production and the decrease of mitochondria membrane potential (ΔΨm) were observed by flow cytometric analysis in U-2 OS cells after GdCl3 exposure. Western blot analyses demonstrated that the levels of Fas, FasL, cytochrome c, Apaf-1, GADD153 and GRP78 were upregulated in GdCl3-treated U-2 OS cells. In conclusion, death receptor, mitochondria-dependent and endoplasmic reticulum (ER) stress pathways contribute to GdCl3-induced apoptosis in U-2 OS cells. GdCl3 might have potential to be used in treatment of osteosarcoma patients.

YC-1 induces G0/G1phase arrest and mitochondria-dependent apoptosis in cisplatin-resistant human oral cancer CAR cells

“…The mean fluorescence intensity (MFI) was quantified by BD CellQuest Pro software (BD Biosciences, San Jose, CA, USA) after analysis by flow cytometry [86, 105, 106]. …”

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

“…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). The exact molecular mechanism of GdCl 3 that…”

“…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).…”

“…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). 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).…”

“…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).…”