Ginsenoside-Rh2-Induced Mitochondrial Depolarization and Apoptosis Are Associated with Reactive Oxygen Species- and Ca²⁺-Mediated c-Jun NH₂-Terminal Kinase 1 Activation in HeLa Cells

Abstract

We show here that Ca 2ϩ and reactive oxygen species (ROS) are involved in the up-regulation of c-Jun NH 2 -terminal kinase 1 (JNK1) activity during apoptosis induced by ginsenoside Rh2 (G-Rh2) in HeLa, MCF10A-ras, and MCF7 cells. Addition of antioxidants such as N-acetyl-L-cysteine or catalase attenuates G-Rh2-induced ROS generation, JNK1 activation, and apoptosis. The overexpression of catalase down-regulates caspase-3 and JNK1 activities. G-Rh2 treatment of cells results in mitochondrial depolarization, second mitochondrial activator of caspase release, and translocation of Bax into the mitochondria, and these events are inhibited by antioxidants. Ca 2ϩ is also involved in mitochondrial depolarization during G-Rh2-induced apoptosis. These results suggest that ROS and Ca 2ϩ are important signaling intermediates leading to stress-activated protein kinase/extracellular signal-regulated kinase kinase 1/JNK1 activation and depolarization of the mitochondrial membrane potential in G-Rh2-induced apoptosis.

Ginsenoside Rh2 induces Bcl‐2 family proteins‐mediated apoptosis in vitro and in xenografts in vivo models

“…Rh2-mediated alteration in levels of Bcl-2 family proteins has been described in other cell types. For instance, apoptosis induction by Rh2 in HeLa human ovarian cancer cells correlated with up-regulation and translocation of Bax into the mitochondria which leads to mitochondria depolarization [Ham et al, 2006]. The present study revealed that Rh2 treatment causes mitochondrial translocation of Bax to trigger the release of cytochrome c from mitochondria to the cytosol, leading to activation of caspases.…”

Pro-Oxidant Natural Products as Anticancer Agents

“…(Rutaceae) [189,190] Hydroxytyrosol Simple Phenol Olea europaea (Oleaceae) [191] Icariin Flavonol glycoside Epimedium spp. (Berberidaceae) [192] Isoeugenol Phenylpropanoid Eugenia caryophyllata (Myrtaceae) [193,194] Isoliquiritigenin Chalcone Glycyrrhiza glabra (Fabaceae) [178,195] Juglone Naphtoquinone Juglans regia (Juglandaceae) [196,197] Kaempferol Flavonol Kaempferia galanga (Zingiberaceae), widespread [198,199] Liquiritigenin Flavanone Glycyrrhiza glabra (Fabaceae) [200] Luteolin Flavone Reseda luteola (Resedaceae), widespread [201,202] Malvidin Anthocyanidin Althaea rosea (Malvaceae) [157,203] Malvidin Ginkgolide B Diterpenoid Ginkgo biloba (Ginkgoaceae) [284,285] Ginsenoside RH-2 Triterpenoid saponin Ginkgo biloba (Ginkgoaceae) [286,287] Glaucocalyxin A Diterpenoid Rabdosia japonica var. glaucocalyx (Lamiaceae) [288] Guggulsterone Triterpenoid Commiphora mukul (Burseraceae) [289,290] Gypenosides Triterpenoid Gynostemma pentaphyllum (Cucurbitaceae) [291,292] Helenalin Sesquiterpenoid Arnica spp.…”

Isoobtusilactone A Induces Cell Cycle Arrest and Apoptosis through Reactive Oxygen Species/Apoptosis Signal-Regulating Kinase 1 Signaling Pathway in Human Breast Cancer Cells

“…Oxidative stress occurs when this critical balance is disrupted because of excess ROS, antioxidant depletion, or both. Evidence is accumulating to indicate that chemotherapeutic agents may be selectively toxic to tumor cells because they increase oxidant stress and enhance these already stressed cells beyond their limit (8,9). Cytotoxic ROS signaling seems to be mediated in part by activation of the apoptosis signal-regulating kinase 1 (ASK1)/mitogenactivated protein kinase (MAPK) signaling pathway (4,(10)(11)(12).…”