Novel triterpenoid AECHL-1 induces apoptosis in breast cancer cells by perturbing the mitochondria–endoplasmic reticulum interactions and targeting diverse apoptotic pathways

Sawant, Mithila A.; Dasgupta, Aparajita; Lavhale, Manish S; Sitasawad, Sandhya L.

doi:10.1016/j.bbagen.2016.02.002

Cited by 15 publications

(13 citation statements)

References 48 publications

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“…Surprisingly, Profilin in this case was found to be down regulated too, which could be attributed to a global protein down regulation observed in these tumors after one month of treatment, especially when they were already undergoing recession16. These, AECHL-1 mediated, inhibitory effects were also responsible for the decrease in presence of metastatic lesions in the lungs of animals, injected with MDA-MB-231 through the tail vein.…”

Section: Discussionmentioning

confidence: 78%

“…Since TNF-α, through NF-κB, is known to regulate the expression and activity of β-catenin, Snail and GSK-3β40, our results indicate that NF-κB plays an indispensable role in implementing the anti-cancer program triggered by AECHL-1. A previous study concerning the apoptosis inducing mechanism of AECHL-1 too highlighted the involvement of NF-κB16.…”

Section: Discussionmentioning

confidence: 95%

“…Natural compounds have been shown to possess enormous potential as anti-proliferative as well as anti-metastatic agents against multiple cancer types121314. Earlier, we had reported the anticancer activity of a novel triterpenoid, AECHL-1, isolated from the root bark of Ailanthus excelsa RoxB15 and recently we gained further insights into its mechanism of action, and demonstrated that AECHL-1 could trigger apoptosis in breast cancer cells via mitochondrial perturbations and elevated ER stress16. Another line of investigation revealed that AECHL-1 inhibits tumor angiogenesis of breast cancer cells via cytoskeletal disruption17.…”

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confidence: 99%

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AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics

Dasgupta

Sawant

Kavishwar

et al. 2016

Sci Rep

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Triple negative breast cancer (TNBC) features among the most aggressive manifestations of cancer due to its enhanced metastatic potential and immunity to therapeutics which target hormone receptors. Under such scenarios, anti-cancer compounds with an ability to influence multiple targets, or an entire process, will have an advantage over specific signal transduction inhibitors. To counter the metastatic threat it is essential to target cellular components central to the processes of cancer cell migration and adaptation. Our previous work on a novel triterpenoid, AECHL-1, explored its anti-cancer potential, and linked it to elevated ER stress in cancer cells, while its anti-angiogenic potential was credited for its ability to manipulate the cytoskeleton. Here, we broaden its range of action by showing that it curbs the metastatic ability of TNBC cells, both in vitro in MDA-MB-231 cell line and in vivo, in mouse models of metastasis. AECHL-1 does so by disrupting the cytoskeletal network, and also suppressing NF-κB and β-Catenin mediated key molecular pathways. These activities also contributed to AECHL-1 mediated suppression of TGF-β/TNF-α induced Epithelial to Mesenchymal Transition (EMT) and cancer stem cell characteristic. Thus, we present AECHL-1 as a promising therapeutic inhibitor of metastatic disease.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics

Dasgupta

Sawant

Kavishwar

et al. 2016

Sci Rep

Self Cite

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“…Calcium can regulate both cell survival and death [27]. Indeed, deregulation of Ca 2+ homeostasis is one of the first hallmarks of apoptosis [28]. Cancer cells can evade apoptosis through decreased expression of Ca 2+ -permeable channels to prevent calcium influx, acquire resistance to prolonged endoplasmic reticulum calcium deficiency, and down-regulate mitochondrial calcium uniporters [29].…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in the acylphosphatase 2 gene and the risk of breast cancer in a Han Chinese population

Zhang

Deng

et al. 2016

Oncotarget

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We performed a case-control study to investigate the associations between seven single nucleotide polymorphisms (SNPs) in the acylphosphatase 2 (ACYP2) gene and breast cancer (BC) risk in a Han Chinese population. There were 183 BC cases and 195 healthy controls included in the study. The SNPs were genotyped using the Sequenom MassARRAY platform. Logistic regression (adjusted for age group, body mass index [BMI], and menopause status), was used to evaluate the associations between the various genotypes and BC risk. Statistical analysis revealed that rs12621038 was associated with a decreased risk of BC in the allele (T vs. C: odds ratio [OR] = 0.71, 95% confidence interval [95% CI] = 0.52–0.94; p = 0.016), homozygous (TT vs. CC: OR = 0.47, 95% CI = 0.24–0.85; p = 0.014), dominant (OR = 0.62; 95% CI = 0.40−0.96; p = 0.032), and additive (OR = 0.68; 95% CI = 0.50–0.92; p = 0.012) models. In addition, we found that rs1682111 and rs17045754 were associated with the risk of BC and correlated with recurrence, and that rs6713088 correlated with tumor size. In sum, our findings reveal significant associations between SNPs in the ACYP2 gene and BC risk in a Han Chinese population.

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“…Annexin V can bind with phosphatidyl serine and Annexin V conjugates (Annexin V/fluorescein isothiocyanate) are commonly used for detecting apoptosis by FCM (Zhang, Gurtu, Kain, & Yan, ). FCM has been used to confirm apoptosis by caspase activation, mitochondrial membrane potential, mitochondrial morphology and cytosolic Ca 2+ concentration in a novel triterpenoid, AECHL‐1, treated MCF‐7 and MDA‐MB‐231 breast cancer cells in a study carried out by Sawant, Dasgupta, Lavhale, and Sitasawad (). Assessment of the cell cycle and apoptosis (cells stained with Annexin V/PI) using FCM has been carried out in prostate cancer (LNCaP) cells by Rodriguez‐Garcia et al ().…”

Section: Detection Of Apoptosismentioning

confidence: 99%

In vitro assays and techniques utilized in anticancer drug discovery

Ediriweera

Tennekoon

Samarakoon

2018

J of Applied Toxicology

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Development of a cancer is a multistep process and six major hallmarks of cancer that are known to control malignant transformation have been described. Anticancer drug development is a tedious process, requiring a number of in vitro, in vivo and clinical studies. In vitro assays provide an initial platform for cancer drug discovery approaches. A wide range of in vitro assays/techniques have been developed to evaluate each hallmark feature of cancer and selection of a particular in vitro assay or technique mainly depends on the specific research question (s) to be examined. In the present review, we have described some commonly utilized in vitro assays and techniques used to examine cell viability/proliferation, apoptosis, cellular senescence, invasion and migration, oxidative stress and antioxidant effects, gene and protein expression, angiogenesis and genomic alterations in cancer drug discovery. Additionally, uses of modern techniques such as high throughput screening, high content screening and reporter gene assays in cancer drug discovery have also been described.

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Novel triterpenoid AECHL-1 induces apoptosis in breast cancer cells by perturbing the mitochondria–endoplasmic reticulum interactions and targeting diverse apoptotic pathways

Abstract: Aggravation of ER stress by AECHL-1 uncovers a novel pathway for selective elimination of cancer cells.

Cited by 15 publications

References 48 publications

AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics

AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics

Genetic variants in the acylphosphatase 2 gene and the risk of breast cancer in a Han Chinese population

In vitro assays and techniques utilized in anticancer drug discovery

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