SERCA plays a crucial role in the toxicity of a betulinic acid derivative with potential antimalarial activity

Diedrich, Denise; Wildner, Andreia C.; Silveira, Thayse F.; Silva, Gloria N. S.; Santos, Francine dos; Silva, Elenilson Figueiredo da; Canto, Vanessa Petry do; Visioli, Fernanda; Gosmann, Grace; Bergold, Ana María; Zimmer, Aline Rigon; Netz, Paulo Augusto; Gnoatto, Simone Cristina Baggio

doi:10.1016/j.cbi.2018.03.014

Cited by 10 publications

(9 citation statements)

References 23 publications

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“…As a result of their action, an increase of cytoplasmic [Ca 2+ ] and subsequent activation of UPR were observed [89, 91]. It was shown that triterpenoids could also act on Ca 2+ homeostasis – SM analogs CDDO and CDDO-Me were found to induce the release of intracellular calcium stores into the cytoplasm of tumor cells (1–10 μM (COLO 16 skin carcinoma cells (1 h)) and 1.5 μM (MDA-MB 435 breast cancer cells (2–6 h)), respectively) [92, 93]; another semisynthetic triterpenoid LAFIS13 and a range of triterpenoid saponins can directly bind to SERCA [94] and effectively inhibit its activity [95, 96]. Geldanamycin is a selective inhibitor of Hsp90 and ER Hsp90 paralog Grp94, directly binding to the N-domain and competing for the ATP binding site of the proteins [97].…”

Section: Resultsmentioning

confidence: 99%

“…Results obtained with docking studies are in line with published data. It was shown previously that a range of triterpenoids could bind to SERCA and inhibit its pump activity [94–96]. Moreover, the increase of intracellular Ca 2+ concentration induced by CDDO-Me (1.5 μM; MDA-MB 435/MDA-MB 231/MCF-7 breast cancer cells (1–6 h)) was found to be independent of ER resident Ca 2+ release receptor RyR [93] and, therefore, could be explained by other mechanisms, such as the dysregulation of reverse pumping of Ca 2+ from the cytoplasm to the ER, performed by SERCA.…”

Section: Discussionmentioning

confidence: 99%

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Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis

et al. 2019

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Semisynthetic triterpenoids, bearing cyano enone functionality in ring A, are considered now as novel promising anti-tumor agents. However, despite the large-scale studies, their effects on cervical carcinoma cells and, moreover, mechanisms underlying cell death activation by such compounds in this cell type have not been fully elucidated. In this work, we attempted to reconstitute the key pathways and master regulators involved in the response of human cervical carcinoma KB-3-1 cells to the novel glycyrrhetinic acid derivative soloxolone methyl (SM) by a transcriptomic approach. Functional annotation of differentially expressed genes, analysis of their cis - regulatory sequences and protein-protein interaction network clearly indicated that stress of endoplasmic reticulum (ER) is the central event triggered by SM in the cells. A range of key ER stress sensors and transcription factor AP-1 were identified as upstream transcriptional regulators, controlling the response of the cells to SM. Additionally, by using Gene Expression Omnibus data, we showed the ability of SM to modulate the expression of key genes involved in regulation of the high proliferative rate of cervical carcinoma cells. Further Connectivity Map analysis revealed similarity of SM's effects with known ER stress inducers thapsigargin and geldanamycin, targeting SERCA and Grp94, respectively. According to the molecular docking study, SM could snugly fit into the active sites of these proteins in the positions very close to that of both inhibitors. Taken together, our findings provide a basis for the better understanding of the intracellular processes in tumor cells switched on in response to cyano enone-bearing triterpenoids.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis

et al. 2019

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“…In this regard, LAFIS13 showed high toxicity at doses of 2000 and 300 mg/kg and caused the death of all the exposed animals. However, at 50 mg/kg, LAFIS13 was not lethal, and no signs of toxicity were observed [36]. According to the OECD-423 protocol, LAFIS13 LD 50 ranges between 300 and 50 mg/kg; thus, it fits the class 3 of chemical agents, as reported by the Globally Harmonized Classification System (GHS).…”

Section: Discussionmentioning

confidence: 89%

“…It has already been demonstrated in Candida albicans that terpenes have antifungal and antibiofilm effects [35]. LAFIS13, a pentacyclic triterpene, was selected among the other terpenes due to its recently described promising properties and the absence of a negative impact on hematological and biochemical parameters [36]. LAFIS13 was obtained as described previously [37].…”

Section: Selection Of the Ba Active Derivative Lafis13 As A Potentialmentioning

confidence: 99%

A Highly Active Triterpene Derivative Capable of Biofilm Damage to Control Cryptococcus spp.

et al. 2019

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Cryptococcus neoformans is an encapsulated yeast responsible for more than 180,000 deaths per year. The standard therapeutic approach against cryptococcosis is a combination of amphotericin B with flucytosine. In countries where cryptococcosis is most prevalent, 5-fluorocytosine is rarely available, and amphotericin B requires intravenous administration. C. neoformans biofilm formation is related to increased drug resistance, which is an important outcome for hospitalized patients. Here, we describe new molecules with anti-cryptococcal activity. A collection of 66 semisynthetic derivatives of ursolic acid and betulinic acid was tested against mature biofilms of C. neoformans at 25 µM. Out of these, eight derivatives including terpenes, benzazoles, flavonoids, and quinolines were able to cause damage and eradicate mature biofilms. Four terpene compounds demonstrated significative growth inhibition of C. neoformans. Our study identified a pentacyclic triterpenoid derived from betulinic acid (LAFIS13) as a potential drug for anti-cryptococcal treatment. This compound appears to be highly active with low toxicity at minimal inhibitory concentration and capable of biofilm eradication.

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“…Celastrol increases leptin sensitivity and suppresses food intake in obese mice through an unknown molecular mechanism (Liu et al, 2015). Artemisinin, an antimalarial drug isolated from Artemisia annua L, interacts with several proteins, such as TCTP, SERCA orthologue PfATP6, and P. falciparum cysteine proteases (Diedrich et al, 2018). However, the described interactions between artemisinin and other proteins may not accurately explain its anticancer effects.…”

Section: Introductionmentioning

confidence: 99%

The Natural Compound Oblongifolin C Exhibits Anticancer Activity by Inhibiting HSPA8 and Cathepsin B In Vitro

Han

et al. 2020

Front. Pharmacol.

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PPAPs (Polycyclic polyprenylated acylphloroglucinols) are a class of compounds with diverse bioactivities, including anticancer effects. Oblongifolin C (OC) is a PPAP isolated from the plant of Garcinia yunnanensis Hu. We previously discovered that OC induces apoptosis, inhibits autophagic flux, and attenuates metastasis in cancer cells. However, the protein targets and the detailed mechanism of action of OC remain unclear. To identify protein targets of OC, a non-labeled protein fishing assay was performed, and it was found that OC may interact with several proteins, including the heat shock 70 kDa protein 8 (HSPA8). Expanding on our previous studies on protein cathepsin B, this current study applied Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) to confirm the potential binding affinity between OC and two protein targets. This study highlights the inhibitory effect of OC on HSPA8 in cancer cells under heat shock stress, by specifically inhibiting the translocation of HSPA8. OC also enhanced the interaction between HSPA8, HSP90, and p53, upregulated the expression of p53 and significantly promoted apoptosis in cisplatin-treated cells. Additionally, a flow cytometry assay detected that OC sped up the apoptosis rate in HSPA8 knockdown A549 cells, while overexpression of HSPA8 delayed the OC-induced apoptosis rate. In summary, our results reveal that OC potentially interacts with HSPA8 and cathepsin B and inhibits HSPA8 nuclear translocation and cathepsin B activities, altogether suggesting the potential of OC to be developed as an anticancer drug.

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SERCA plays a crucial role in the toxicity of a betulinic acid derivative with potential antimalarial activity

Cited by 10 publications

References 23 publications

Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis

Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis

A Highly Active Triterpene Derivative Capable of Biofilm Damage to Control Cryptococcus spp.

The Natural Compound Oblongifolin C Exhibits Anticancer Activity by Inhibiting HSPA8 and Cathepsin B In Vitro

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