Resveratrol Induces Apoptosis through ROS-Dependent Mitochondria Pathway in HT-29 Human Colorectal Carcinoma Cells

Juan, M. Emília; Wenzel, U.; Daniel, Hannelore; Planas, Joana M.

doi:10.1021/jf800175a

Cited by 182 publications

(127 citation statements)

References 32 publications

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“…Recent evidence has demonstrated that ROS serve as messengers for normal signal transductions at lower concentrations; at higher concentrations, however, they become toxic and induce cell death through various signaling pathways (8,22). As cancer cells contain higher level of ROS than normal cells, they can be easily poisoned by the phytochemical targeting ROS metabolism (17,18).…”

Section: Discussionmentioning

confidence: 99%

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Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

et al. 2012

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Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time‐ and dose‐dependent manner. The alantolactone‐induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl‐2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP‐ribose) polymerase. This alantolactone‐induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N‐acetyl‐L‐cysteine, whereas other antioxidant (polyethylene glycol (PEG)‐catalase and PEG‐superoxide‐dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF‐κB into nucleus; however, NF‐κB inhibitor, SN50 failed to potentiate alantolactone‐induced apoptosis indicating that alantolactone induces NF‐κB‐independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, alantolactone may become a potential lead compound for future development of antiglioma therapy. © © 2012 IUBMB Life, 64(9): 783–794, 2012

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Section: Discussionmentioning

confidence: 99%

“…Alantolactone, a sesquiterpene lactone compound, has been reported to possess antifungal, antibacteria, and antihelminthic properties. Very recently, it has been shown to induce ROS generation and apoptosis in HL-60 cells (22). However, the exact role of ROS in cell death induced by alantolactone has not been explored.…”

Section: Discussionmentioning

confidence: 99%

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

et al. 2012

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“…Recent research has shown that natural bioactive compounds targeting ROS metabolism can selectively kill cancer cells by increasing the ROS level above a toxic threshold. As cancer cells contain higher levels of endogenous ROS, the toxic threshold can easily be achieved in cancer cells by targeting them with exogenous ROS-generating phytochemicals [1,7,8] . Prostate cancer cells have been reported to contain higher level of ROS [9] ; therefore, targeting ROS metabolism in prostate cancer cells may be an effective treatment.…”

Section: Original Articlementioning

confidence: 99%

Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro

Yang

Khan

et al. 2016

Acta Pharmacol Sin

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Aim: Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from the Chinese herbal medicine Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), has shown anticancer activities in various cancer cell lines. The aim of this study was to investigate the anticancer activity and molecular targets of TBMS1 in human prostate cancer cells in vitro. Methods: DU145 and P3 human prostate cancer cells were treated with TBMS1. Cell viability and apoptosis were detected. ROS generation, mitochondrial membrane potential and cell cycle profile were examined. Western blotting was used to measure the expression of relevant proteins in the cells. Results: TBMS1 (5-100 μmol/L) significantly suppressed the viability of DU145 and P3 cells with IC 50 values of approximately 10 and 20 μmol/L, respectively. Furthermore, TBMS1 dose-dependently induced apoptosis and cell cycle arrest at G 0 /G 1 phase in DU145 and P3 cells. In DU145 cells, TBMS1 induced mitochondrial apoptosis, evidenced by ROS generation, mitochondrial dysfunction, endoplasmic reticulum stress, modulated Bcl-2 family protein and cleaved caspase-3, and activated ASK-1 and its downstream targets p38 and JNK. The G 0 /G 1 phase arrest was linked to increased expression of p53 and p21 and decreased expression of cyclin E and cdk2. Co-treatment with Z-VAD-FMK (pan-caspase inhibitor) could attenuate TBMS1-induced apoptosis but did not prevent G 0 /G 1 arrest. Moreover, co-treatment with NAC (ROS scavenger), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor) or salubrinal (ER stress inhibitor) significantly attenuated TBMS1-induced apoptosis. Conclusion: TBMS1 induces oxidative stress-mediated apoptosis in DU145 human prostate cancer cells in vitro via the mitochondrial pathway.

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“…Resveratrol is an established cytotoxic agent in prostate, 23 breast, 33 ovarian, 34 colon, 35 lung, 36 heptatic, and brain cancer cells 37 and is a proposed chemopreventive agent. 22 As a component of grape skins, resveratrol is already in the diet, 38 implying it may be well tolerated if used in long-term clinical dosing.…”

Section: U0126 Inhibits Resveratrol Induced Apoptosismentioning

confidence: 99%

A metabolic perturbation by U0126 identifies a role for glutamine in resveratrol-induced cell death

Freeman

Kim

Lisanti

et al. 2011

Cancer Biology & Therapy

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Recent evidence has identified substantial overlap between metabolic and oncogenic biochemical pathways, suggesting novel approaches to cancer intervention. For example, cholesterol lowering statins and the antidiabetes medication metformin both act as chemopreventive agents in prostate and other cancers. The natural compound resveratrol has similar properties: increasing insulin sensitivity, suppressing adipogenesis, and inducing apoptotic death of cancer cells in vitro. However, in vivo tumor xenografts acquire resistance to resveratrol by an unknown mechanism, while mouse models of metabolic disorders respond more consistently to the compound. Here we demonstrate that castrationresistant human prostate cancer C4-2 cells are more sensitive to resveratrol-induced apoptosis than isogenic androgendependent LNCaP cells. The MEK inhibitor U0126 antagonized resveratrol-induced apoptosis in C4-2 cells, but this effect was not seen with other MEK inhibitors. U0126 was found to inhibit mitochondrial function and shift cells to aerobic glycolysis independently of MEK. Mitochondrial activity of U0126 arose through decomposition, producing both mitochondrial fluorescence and cyanide, a known inhibitor of complex IV. Applying U0126 mitochondrial inhibition to C4-2 cell apoptosis, we tested the possibility that glutamine supplementation of citric acid cycle intermediate aketoglutarate may be involved. Suppression of the conversion of glutamate to a-ketoglutarate antagonized resveratrolinduced death in C4-2 cells. A similar effect was also seen by reducing extracellular glutamine concentration in the culture medium, suggesting that resveratrol-induced death is dependent on glutamine metabolism, a process frequently dysregulated in cancer. Further work on resveratrol and metabolism in cancer is warranted to ascertain if the glutamine dependence has clinical implications.

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Resveratrol Induces Apoptosis through ROS-Dependent Mitochondria Pathway in HT-29 Human Colorectal Carcinoma Cells

Cited by 182 publications

References 32 publications

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro

A metabolic perturbation by U0126 identifies a role for glutamine in resveratrol-induced cell death

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