Sesquiterpene lactones as drugs with multiple targets in cancer treatment

Kreuger, Maria Regina Orofino; Grootjans, Sasker; Biavatti, Maique W.; Vandenabeele, Peter; D’Herde, Katharina

doi:10.1097/cad.0b013e328356cad9

Cited by 183 publications

(85 citation statements)

References 110 publications

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“…To test the hypothesis that activation of NF-kB is necessary for the inhibition of cell proliferation by chloroquine and 6-AN, we treated the cells with parthenolide, which inhibits both p65/RelA and caspase-1 via alkylation 16 . Parthenolide restored proliferation in cells treated with CQ and 6-AN (Figure S8).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, the combination of chloroquine and 6-AN triggered activation of the NF-kB and inflammasome pathways in a TSC2-dependent manner, and parthenolide 16 , which inhibits both NF-kB and caspase-1, rescued proliferation under these conditions. Inflammasomes are multiprotein complexes that mediate the cleavage and activation of caspase-1, thereby stimulating an inflammatory response and/or programmed cell death 20 .…”

Section: Discussionmentioning

confidence: 99%

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Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Parkhitko

Priolo

Coloff

et al. 2014

Molecular Cancer Research

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The mammalian target of rapamycin complex 1 (mTORC1) is hyperactive in many human cancers and in tuberous sclerosis complex (TSC). Autophagy, a key mTORC1 targeted process, is a critical determinant of metabolic homeostasis. Metabolomic profiling was performed to elucidate the cellular consequences of autophagy dysregulation under conditions of hyperactive mTORC1. It was discovered that TSC2-null cells have distinctive autophagy-dependent pentose phosphate pathway (PPP) alterations. This was accompanied by enhanced glucose uptake and utilization, decreased mitochondrial oxygen consumption, and increased mitochondrial ROS production. Importantly, these findings revealed that the PPP is a key autophagy-dependent compensatory metabolic mechanism. Furthermore, PPP inhibition with 6-aminonicotinamide (6-AN) in combination with autophagy inhibition suppressed proliferation and prompted the activation of NF-kB and CASP1 in TSC2-deficient, but not TSC2-proficient cells. These data demonstrate that TSC2-deficient cells can be therapeutically targeted, without mTORC1 inhibitors, by focusing on their metabolic vulnerabilities. Implications: This study provides proof-of-concept that therapeutic targeting of diseases with hyperactive mTORC1 can be achieved without the application of mTORC1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Parkhitko

Priolo

Coloff

et al. 2014

Molecular Cancer Research

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“…Initial bioassay screening results showed the majority of the isolated sesquiterpene lactones to be cytotoxic toward HT-29 colon cancer cells 10 and to inhibit NFκB activity 9 . Similarly, we found that goyazensolide isolated from Piptocoma rufescens efficiently inhibits proliferation of NF2 -deficient schwannoma and meningioma cells and reduces the expression of the p65 subunit of NFκB.…”

Section: Discussionmentioning

confidence: 99%

“…Cucurbitacins, initially isolated from plants of the family Cucurbitaceae, are known to induce cancer cell death and inhibit the JAK-STAT and MAPK signaling pathways 6–7 ; cucurbitacin D, one of the most potent biologically-active cucurbitacins, has been shown to inhibit proliferation of HT-29 human colon carcinoma cells 8 . Like cucurbitacins, sesquiterpene lactones comprise a large diverse group of compounds; of which, some possess antitumor effects and can suppress NFκB activity 9 . Goyazensolide, a sesquiterpene lactone isolated from Piptocoma rufescens , has also been shown to be highly cytotoxic to HT-29 cells 10 .…”

Section: Introductionmentioning

confidence: 99%

Natural Compounds as Potential Treatments of NF2-Deficient Schwannoma and Meningioma

Spear

Burns

Oblinger

et al. 2013

Otology &Amp; Neurotology

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Hypothesis Cucurbitacin D and goyazensolide, two plant-derived natural compounds, possess potent growth-inhibitory activity in schwannoma and meningioma cells. Background Currently, no FDA-approved drugs are available for neurofibromatosis type 2 (NF2)-associated schwannomas and meningiomas. Selected natural compounds with antineoplastic activity, such as cucurbitacin and goyazensolide, may be developed as potential treatments for these tumors. Methods The Nf2-deficient mouse schwannoma Sch10545 and human benign meningioma Ben-Men-1 cells were treated with various concentrations of cucurbitacin D and goyazensolide. The effect on cell proliferation was determined using resazurin assays. Flow cytometry was used to assess the cell cycle profiles. Western blot analysis was performed to investigate the expression of various signal molecules related to the cell cycle and the AKT pathway. Results Cucurbitacin D inhibited proliferation of Sch10545 cells (IC50 ~0.75 μM) and Ben-Men-1 cells (IC50 ~0.2 μM). Goyazensolide also reduced cell proliferation of Sch10545 cells (IC50 ~0.9 μM) and Ben-Men-1 cells (IC50 ~1 μM). The G2/M population increased in both Sch10545 and Ben-Men-1 cells treated with cucurbitacin D or goyazensolide around the IC50. Cucurbitacin and goyazensolide substantially reduced the levels of cyclins E and A in treated Sch10545 and Ben-Men-1 cells. Cucurbitacin D also inhibited cyclin B, phospho-AKT and phospho-PRAS40 expression. In addition, goyazensolide reduced the levels of phospho-AKT and NFκB and increased the expression of pro-apoptotic Bim in Sch10545 and Ben-Men-1 cells. Conclusions Both cucurbitacin D and goyazensolide effectively inhibit proliferation of NF2-deficient schwannoma and meningioma cells, suggesting that these natural compounds should be further evaluated as potential treatments for NF2-related tumors.

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“…The essential oils of the aerial parts of A. graveolens contain also monoterpens and sesquiterpenes including oxygenated sesquiterpenes (6-oxocyclonerolidol and 6-hydroxycyclonerolidol) as the major components [4]. Sesquiterpene lactones are often used in traditional medicine against inflammation and cancer; for example artemisinin, thapsigargin and parthenolide are in clinical trials as they are selective toward tumor and cancer stem cells [5,6]. A. graveolens extract exhibit antimicrobial activity [7] and anti-fungal activity [8], however, there are no published reports on A. graveolens extracts as possessing anti-cancer activity.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mode of Action of Asteriscus graveolens as an Anticancer Agent

Tayeh

Dudai

Schechter

et al. 2018

IJMS

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Asteriscus graveolens (A. graveolens) plants contain among other metabolites, sesquiterpene lactone asteriscunolide isomers (AS). The crude extract and its fractions affected the viability of mouse BS-24-1 lymphoma cells (BS-24-1 cells) with an IC50 of 3 μg/mL. The fraction was cytotoxic to cancer cells but not to non-cancerous cells (human induced pluripotent stem cells); its activity was accompanied by a concentration- and time-dependent appearance of apoptosis as determined by DNA fragmentation and caspase-3 activity. High levels of Reactive Oxygen Species (ROS) were rapidly observed (less than 1 min) after addition of the fraction followed by an increase in caspase-3 activity three hours later. Comparison of RNA-seq transcriptome profiles from pre-and post-treatment of BS-24-1 cells with crude extract of A. graveolens yielded a list of 2293 genes whose expression was significantly affected. This gene set included genes encoding proteins involved in cell cycle arrest, protection against ROS, and activation of the tumor suppressor P53 pathway, supporting the biochemical findings on ROS species-dependent apoptosis induced by A. graveolens fraction. Interestingly, several of the pathways and genes affected by A. graveolens extract are expressed following treatment of human cancer cells with chemotherapy drugs. We suggest, that A. graveolens extracts maybe further developed into selective chemotherapy.

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Sesquiterpene lactones as drugs with multiple targets in cancer treatment

Cited by 183 publications

References 110 publications

Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Natural Compounds as Potential Treatments of NF2-Deficient Schwannoma and Meningioma

Molecular Mode of Action of Asteriscus graveolens as an Anticancer Agent

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