Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment

Salvador, Jorge A. R.; Leal, Ana S.; Valdeira, Ana S.; Gonçalves, Bruno M. F.; Alho, Daniela P.S.; Figueiredo, Sandra A. C.; Silvestre, Samuel; Mendes, Vanessa I.S.

doi:10.1016/j.ejmech.2017.07.013

Cited by 138 publications

(95 citation statements)

References 248 publications

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“…As a negative control, erlotinib showed no effect on viability (Figure b,c). Previous studies have shown that UA was less toxic than AA to normal cells (Salvador et al, ; Vo, Fukushima, & Muranaka, ). Consistent with these findings, we found that UA had lower toxicity than AA in human normal lung epithelial (BEAS‐2B) cells (Figure d).…”

Section: Resultsmentioning

confidence: 87%

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Yang

Chen

Zhou

et al. 2019

British J Pharmacology

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Background and Purpose In non‐small‐cell lung carcinoma (NSCLC) patients, the L858R/T790M mutation of the epithelial growth factor receptor (EGFR) is a major cause of acquired resistance to EGFR‐TKIs treatment that limits their therapeutic efficacy. Identification of drugs that can preferentially kill the NSCLC harbouring L858R/T790M mutation is therefore critical. Here, we have evaluated the effects of ursolic acid, an active component isolated from herbal sources, on erlotinib‐resistant H1975 cells that harbour the L858R/T790M mutation. Experimental Approach Gene expression omnibus (GEO) profiles analyses was applied to detect differentially expressed genes in NSCLC cells harbouring EGFR mutation. AnnexinV‐FITC/PI, TUNEL staining, MTT, wound healing, RT‐PCR, qRT‐PCR, western blots, immunostaining, dual‐luciferase reporters and ChIP‐PCR were utilized to investigate the effects of ursolic acid in vitro and in vivo. Key Results The cancer/testis antigen family 45 member A2 (CT45A2) was highly expressed in H1975 cells. Ectopic expression of CT45A2 in H1975 cells increased cell proliferation and motility in vitro. Silencing the CT45A2 expression strongly attenuated H1975 cells motility and growth. The anti‐cancer effect of ursolic acid was critically dependent on CT45A2 expression in H1975 cells. Ursolic acid suppressed CT45A2 gene transcription mediated by transcriptional factor TCF4 and β‐catenin signalling. Conclusions and Implications CT45A2 is a novel oncogene for NSCLC with an EGFR T790 mutation. Ursolic acid induced apoptosis and inhibited proliferation of H1975 cells by negatively regulating the β‐catenin/TCF4/CT45A2 signalling pathway. Therefore, ursolic acid may be a potential candidate treatment for NSCLC harbouring the EGFR‐L858R/T790M mutation.

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Section: Resultsmentioning

confidence: 87%

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Yang

Chen

Zhou

et al. 2019

British J Pharmacology

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“…Plant‐derived triterpenoids have been well studied with a wide range of pharmacological activities . Pentacyclic triterpenoids in particular provide an excellent base from which new pharmacological agents can be developed for cancer therapy by modulating multiple signaling pathways related to apoptosis, autophagy, metastasis, and multidrug resistance . However, there has been little or no effort toward the efficacy of pentacyclic triterpenoids against TNF‐targeted biologics, especially regarding RIPK1‐dependent cell death.…”

Section: Introductionmentioning

confidence: 99%

“…25 Pentacyclic triterpenoids in particular provide an excellent base from which new pharmacological agents can be developed for cancer therapy by modulating multiple signaling pathways related to apoptosis, autophagy, metastasis, and multidrug resistance. 26,27 However, there has been little or no effort toward the efficacy of pentacyclic triterpenoids against TNF-targeted biologics, especially regarding RIPK1-dependent cell death. Previously, we isolated several types of novel pentacyclic triterpenoids from Rubia philippinensis (R. philippinensis) including lignans, cyclopeptides, and anthraquinones.…”

Section: Introductionmentioning

confidence: 99%

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

et al. 2020

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In tumor necrosis factor (TNF) signaling, phosphorylation and activation of receptor interacting protein kinase 1 (RIPK1) by upstream kinases is an essential checkpoint in the suppression of TNF‐induced cell death. Thus, discovery of pharmacological agents targeting RIPK1 may provide new strategies for improving the therapeutic efficacy of TNF. In this study, we found that 3‐O‐acetylrubianol C (3AR‐C), an arborinane triterpenoid isolated from Rubia philippinesis, promoted TNF‐induced apoptotic and necroptotic cell death. To identify the molecular mechanism, we found that in mouse embryonic fibroblasts, 3AR‐C drastically upregulated RIPK1 kinase activity by selectively inhibiting IKKβ. Notably, 3AR‐C did not interfere with IKKα or affect the formation of the TNF receptor1 (TNFR1) complex‐I. Moreover, in human cancer cells, 3AR‐C was only sufficient to sensitize TNF‐induced cell death when c‐FLIPL expression was downregulated to facilitate the formation of TNFR1 complex‐II and necrosome. Taken together, our study identified a novel arborinane triterpenoid 3AR‐C as a potent activator of TNF‐induced cell death via inhibition of IKKβ phosphorylation and promotion of the cytotoxic potential of RIPK1, thus providing a rationale for further development of 3AR‐C as a selective IKKβ inhibitor to overcome TNF resistance in cancer therpay.

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“…Pentacyclic triterpenoids are widely represented in natural products and are useful substrates for the synthesis of various important bioactive compounds [1][2][3]. Conjugation of a triterpenoid scaffold with amines, amino acids, and polyamines resulted in a series of anticancer, antimicrobial and antiviral agents [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

A-Ring-Modified Triterpenoids and Their Spermidine–Aldimines with Strong Antibacterial Activity

Казакова

Brunel

Khusnutdinova

et al. 2019

Molbank

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Synthesis of A-ring-modified lupane, oleanane and ursane type triterpenoid conjugates with spermidine through an aldimine linkage or diethylentriamine via an amide bond is described. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. Except for derivatives 1 and 7, all compounds have moderate to weak minimum inhibitory concentrations (MICs) against Gram-positive Staphylococcus aureus bacteria, with MICs varying from 3.125 to 200 µM. Compound 11 is efficient against Escherichia coli and Pseudomonas aeruginosa, with MICs of 25 and 50 µM, respectively, while all other derivatives do not possess important antimicrobial activities against these Gram-negative bacteria.

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Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment

Cited by 138 publications

References 248 publications

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

A-Ring-Modified Triterpenoids and Their Spermidine–Aldimines with Strong Antibacterial Activity

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