Cytotoxic Activity of Germacrane-Type Sesquiterpene Lactones from <i>Dimerostemma aspilioides</i>

Manzano, María Florencia García; Joray, Mariana Belén; Laiolo, Jerónimo; Palacios, Sara M.; Carpinella, María Cecilia

doi:10.1021/acs.jnatprod.0c00115

Cited by 10 publications

(6 citation statements)

References 32 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, sesquiterpene lactones, a class of natural products with excellent anti-inflammatory and anti-tumor activities, have received growing attention from the scientific community ( Shulha and Zidorn, 2019 ; García Manzano et al, 2020 ). Brevilin A is an active sesquiterpene lactone isolated from C. minima , and has been proved to possess anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects ( Chen et al, 2013 ; Zhang et al, 2019 ; Khan et al, 2020 ; Zhou et al, 2020 ; Qin et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling via Targeting IKKα/β

et al. 2022

View full text Add to dashboard Cite

Acute lung injury (ALI) is life-threatening disease characterized by uncontrolled inflammatory response. IKKα/β, the key kinases in the activation of NF-κB pathway, are implicated in inflammatory pulmonary injury, and represent attractive targets for ALI therapy. Brevilin A (BVA) is a sesquiterpene lactone from Centipeda minima, a Chinese herb used to treat inflammatory diseases. This study aims to investigate the inhibition of BVA on ALI, with focus on clarifying the molecular mechanisms involved in BVA-mediated anti-inflammatory activity in macrophages. Briefly, BVA significantly inhibited the production of NO and PGE2 by suppressing iNOS and COX2 expression, and suppressed the mRNA expression of IL-1β, IL-6, and TNFα in LPS/IFNγ-stimulated RAW264.7 macrophages. The anti-inflammatory activity of BVA was further confirmed in LPS/IFNγ-stimulated BMDMs and TNFα/IFNγ-exposed RAW264.7 cells. In vivo, BVA effectively attenuated LPS-induced lung damage, inflammatory infiltration, and production of pro-inflammatory cytokines, including MPO, IL-1β, IL-6, TNFα, and PGE2. Mechanistically, BVA could covalently bind to the cysteine 114 of IKKα/β, and effectively inhibiting the activity and function of IKKα/β, thereby resulting in the suppression of phosphorylation and degradation of IκBα and the subsequent activation of NF-κB signaling. Furthermore, pretreatment of DTT, a thiol ligand donor, significantly abolished BVA-mediated effects in LPS/IFNγ-stimulated RAW264.7 cells, suggesting the crucial role of the electrophilic α, β-unsaturated ketone of BVA on its anti-inflammatory activity. These results suggest that BVA ameliorates ALI through inhibition of NF-κB signaling via covalently targeting IKKα/β, raising the possibility that BVA could be effective in the treatment of ALI and other diseases harboring aberrant NF-κB signaling.

show abstract

Section: Discussionmentioning

confidence: 99%

Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling via Targeting IKKα/β

et al. 2022

View full text Add to dashboard Cite

show abstract

“…These secondary metabolites include flavonoids, alkaloids, acetogenins, and terpenoids. In the latter group, sesquiterpene lactones (SLs) have received considerable attention during the last 17 years [ 8 , 9 , 20 , 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Expanding the Study of the Cytotoxicity of Incomptines A and B against Leukemia Cells

et al. 2022

View full text Add to dashboard Cite

Heliangolide-type sesquiterpene lactones (HTSLs) are phytocompounds with several pharmacological activities including cytotoxic and antitumor activity. Both bioactivities are related to an α-methylene-γ-lactone moiety and an ester group on carbon C-8 in the sesquiterpene lactone (SL) structure. Two HTSLs, incomptines A (AI) and B (IB) isolated from Decachaeta incompta, were evaluated for their cytotoxic activity on three leukemia cell lines: HL-60, K-562, and REH cells. Both compounds were subjected to a molecular docking study using target proteins associated with cancer such as topoisomerase IIα, topoisomerase IIβ, dihydrofolate reductase, methylenetetrahydrofolate dehydrogenase, and Bcl-2-related protein A1. Results show that IA and IB exhibit cytotoxic activity against all cell lines used. The CC50 value of IA was 2–4-fold less than etoposide and methotrexate, two anticancer drugs used as positive controls. The cytotoxic activity of IB was close to that of etoposide and methotrexate. The molecular docking analysis showed that IA and IB have important interaction on all targets used. These findings suggest that IA and IB may serve as scaffolds for the development of new treatments for different types of leukemia.

show abstract

“…The MTT colorimetric assay was performed as previously described ( Joray et al, 2015 , 2017 ; González et al, 2018 ; García Manzano et al, 2020 ). Briefly, 2 × 10 4 cells suspended in 100 μl of complete growth medium were seeded in 96-well plates and 24 h-incubated to allow cell attachment.…”

Section: Methodsmentioning

confidence: 99%

“…In order to evaluate toxicity in peripheral blood mononuclear cells (PBMC), increasing concentrations of compound 3 from 2.5 to 100 μM were tested by MTT assay, as previously reported ( Joray et al, 2015 , 2017 ; García Manzano et al, 2020 ; Laiolo et al, 2021a ) with an incubation period of 48 h. The hemolysis assay was performed with the compound at a maximum concentration of 100 μM ( Joray et al, 2011 ; Funes Chabán et al, 2019a ; Laiolo et al, 2021a , 2021b ). For both experiments, fresh heparinized blood was collected from healthy human volunteer donors not receiving any treatment.…”

Section: Methodsmentioning

confidence: 99%

The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2

Ríos¹,

Lanza

Barbieri

et al. 2022

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat.Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity.Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and β2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool.Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 μg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 μM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 μM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and β2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells.Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.

show abstract

Cytotoxic Activity of Germacrane-Type Sesquiterpene Lactones from Dimerostemma aspilioides

Cited by 10 publications

References 32 publications

Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling via Targeting IKKα/β

Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling via Targeting IKKα/β

Expanding the Study of the Cytotoxicity of Incomptines A and B against Leukemia Cells

The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits angiogenesis by targeting protein kinase C isozymes α and β2

Contact Info

Product

Resources

About