What made sesquiterpene lactones reach cancer clinical trials?

Ghantous, Akram; Gali‐Muhtasib, Hala; Vuorela, Heikki; Saliba, Najat A.; Darwiche, Nadine

doi:10.1016/j.drudis.2010.06.002

Cited by 554 publications

(506 citation statements)

References 64 publications

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“…The cells' endogenous antioxidant defense systems scavenge the ROS to maintain redox balance (10,11). The GSH redox system is one of the important antioxidant defense systems involved in the protection of cells against oxidative damage and in various detoxification systems (12)(13)(14). In addition to GSH, catalase and SOD play important role to detoxify hydrogen peroxide and super-oxides, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, many sesquiterpene lactone compounds have been shown to induce apoptosis in various cancer cell lines through inhibition of NF-jB activation (13,14). We were interested to know if the apoptotic effect of alantolactone in U87 glioblastoma cells is due to its inhibition of NF-jB activation.…”

Section: Alantolactone Induces Apoptosis In U87 Cells Without Affectimentioning

confidence: 99%

“…Over the past few years, a large body of pharmacological studies has provided convincing evidence of the anticancer property of sesquiterpene lactones against various human cancer cell lines (14,15). Alantolactone is one of the major sesquiterpene lactone compounds, isolated from the roots of Anula helenium and possesses multiple biological activities including antibacteria, antifungal, antihelminthic, and antiproliferative (16).…”

Section: Introductionmentioning

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%

Section: Alantolactone Induces Apoptosis In U87 Cells Without Affectimentioning

confidence: 99%

Section: Introductionmentioning

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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“…As prolonged cytosolic Ca 2þ overload and/or ER Ca 2þ depletion represent strong pro-death factors, overactivating the existing Ca 2þ -permeable channels in cancer cells seems in general to be a promising approach for cancer treatment. One of the realizations of this approach is based on using SERCA pump inhibitors from plant-derived sesquiterpene lactones and their derivatives which promote Ca 2þ -dependent apoptosis by preventing ER Ca 2þ uptake [102]. As systemic administration of these compounds can produce significant toxicity to normal cells, to enable their use for PCa treatment it was proposed that they should be combined with a targeting peptide representing the substrate for prostate cancer-specific serine protease, prostate-specific antigen [103].…”

Section: Clinical Prospectsmentioning

confidence: 99%

Remodelling of Ca²⁺transport in cancer: how it contributes to cancer hallmarks?

Prevarskaya

Ouadid-Ahidouch²,

Skryma

et al. 2014

Phil. Trans. R. Soc. B

221

195

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Cancer involves defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to these phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. Cellular Ca 2+ signalling is determined by the concerted action of a molecular Ca 2+ -handling toolkit which includes: active energy-dependent Ca 2+ transporters, Ca 2+ -permeable ion channels, Ca 2+ -binding and storage proteins, Ca 2+ -dependent effectors. In cancer, because of mutations, aberrant expression, regulation and/or subcellular targeting of Ca 2+ -handling/transport protein(s) normal relationships among extracellular, cytosolic, endoplasmic reticulum and mitochondrial Ca 2+ concentrations or spatio-temporal patterns of Ca 2+ signalling become distorted. This causes deregulation of Ca 2+ -dependent effectors that control signalling pathways determining cell's behaviour in a way to promote pathophysiological cancer hallmarks such as enhanced proliferation, survival and invasion. Despite the progress in our understanding of Ca 2+ homeostasis remodelling in cancer cells as well as in identification of the key Ca 2+ -transport molecules promoting certain malignant phenotypes, there is still a lot of work to be done to transform fundamental findings and concepts into new Ca 2+ transport-targeting tools for cancer diagnosis and treatment.

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“…The majority of anticancer drugs are natural products or their derivatives. More than 200 drugs derived from natural products are in preclinical or clinical development and evaluation [8,9].…”

Section: Introductionmentioning

confidence: 99%

<i>Juglans regia</i> Hexane Extract Exerts Antitumor Effect, Apoptosis Induction and Cell Circle Arrest in Prostate Cancer Cells <i>In vitro</i>

Li¹,

Dy²,

Hd³

et al. 2015

Trop. J. Pharm Res

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What made sesquiterpene lactones reach cancer clinical trials?

Cited by 554 publications

References 64 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

Remodelling of Ca²⁺transport in cancer: how it contributes to cancer hallmarks?

<i>Juglans regia</i> Hexane Extract Exerts Antitumor Effect, Apoptosis Induction and Cell Circle Arrest in Prostate Cancer Cells <i>In vitro</i>

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What made sesquiterpene lactones reach cancer clinical trials?

Cited by 554 publications

References 64 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

Remodelling of Ca2+transport in cancer: how it contributes to cancer hallmarks?

<i>Juglans regia</i> Hexane Extract Exerts Antitumor Effect, Apoptosis Induction and Cell Circle Arrest in Prostate Cancer Cells <i>In vitro</i>

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Remodelling of Ca²⁺transport in cancer: how it contributes to cancer hallmarks?