Dentatin isolated from Clausena excavata induces apoptosis in MCF-7 cells through the intrinsic pathway with involvement of NF-κB signalling and G0/G1 cell cycle arrest: A bioassay-guided approach

Arbab, Ismail Adam; Abdul, Ahmad Bustamam; Sukari, Mohd Aspollah; Abdullah, Rasedee; Syam, Suvitha; Kamalıdehghan, Behnam; Ibrahim, Mohamed Yousif; Taha, Manal Mohamed Elhassan; Abdelwahab, Siddig Ibrahim; Ali, Hapipah Mohd; Mohan, Syam

doi:10.1016/j.jep.2012.11.020

Cited by 46 publications

(38 citation statements)

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“…The concentration of DEN that causes death of 50% of tested cells or the IC 50 value of DEN was found to be 5.6 µg/mL. Earlier research performed by [7] revealed similar toxicity against Estrogen Receptor positive (ER+) MCF-7 where IC 50 value was at 6.1 µg/mL. In the study mentioned above, DEN exhibited fewer side-effects on the normal cells in comparison to the cancer cells.…”

Section: Resultsmentioning

confidence: 71%

“…Therefore, exposure time may be prolonged by gradually releasing the DEN from the complex [34]. Moreover, higher resistance was displayed by normal breast MCF10a cells as previously mentioned by [7]. To confirm the selectivity, it can compare the cytotoxicity effects of DEN and DEN-HPβCD complex for cancer cell line with normal cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…ROS is generally localized in the mitochondria and it is important in activating apoptosis and thus inducing cell death [38]. In other words, ROS plays an important role in apoptosis induction by activating the mitochondria intrinsic pathway [7]. Current study revealed that there are increasing in the reactive oxygen species levels in DEN and DEN-HPβCD complex-treated HT-29 cells compared with untreated cells in dose dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…It has been verified that DEN induces apoptosis in human prostate cancer through inhibition of nuclear factor-κB (NF-κB) nuclear translocation and downregulation of the anti-apoptotic molecules such as Bcl-2, Bcl-xL, and Survivin [5]. In addition, using the mitochondrial signaling pathway, DEN has also stimulated apoptosis in human breast cancer MCF-7 and human hepatocellular carcinoma HepG2 cells lines [6,7]. The drugs’ design and development have two critical factors that affect and limit their therapeutic application, represented by poor aqueous solubility and rate of dissolution [8].…”

Section: Introductionmentioning

confidence: 99%

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Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)

Ashwaq

Al‐Qubaisi

Abdullah

et al. 2016

IJMS

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Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPβCD complex leads to cell growth inhibition as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPβCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA)-based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPβCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPβCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future.

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Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)

Ashwaq

Al‐Qubaisi

Abdullah

et al. 2016

IJMS

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“…Caspase 8 activation, which is a major participant in extrinsic pathways, is the result of cell death receptors, such as Fas and TNF-α. Activated caspase 8 also leads to the activity of effector caspases, including caspase 3 and caspase 713414243. The treated MDA-MB-231 cells experienced a significant increase in caspase 9 after 24, 48, and 72 hours of treatment.…”

Section: Discussionmentioning

confidence: 98%

Anticancer activity of a monobenzyltin complex C1 against MDA-MB-231 cells through induction of Apoptosis and inhibition of breast cancer stem cells

Fani

Kamalıdehghan

et al. 2016

Sci Rep

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In the present study, we examined the cytotoxic effects of Schiff base complex, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, and C1 on MDA-MB-231 cells and derived breast cancer stem cells from MDA-MB-231 cells. The acute toxicity experiment with compound C1 revealed no cytotoxic effects on rats. Fluorescent microscopic studies using Acridine Orange/Propidium Iodide (AO/PI) staining and flow cytometric analysis using an Annexin V probe confirmed the occurrence of apoptosis in C1-treated MDA-MB-231 cells. Compound C1 triggered intracellular reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) releases in treated MDA-MB-231 cells. The Cellomics High Content Screening (HCS) analysis showed the induction of intrinsic pathways in treated MDA-MB-231 cells, and a luminescence assay revealed significant increases in caspase 9 and 3/7 activity. Furthermore, flow cytometric analysis showed that compound C1 induced G0/G1 arrest in treated MDA-MB-231 cells. Real time PCR and western blot analysis revealed the upregulation of the Bax protein and the downregulation of the Bcl-2 and HSP70 proteins. Additionally, this study revealed the suppressive effect of compound C1 against breast CSCs and its ability to inhibit the Wnt/β-catenin signaling pathways. Our results demonstrate the chemotherapeutic properties of compound C1 against breast cancer cells and derived breast cancer stem cells, suggesting that the anticancer capabilities of this compound should be clinically assessed.

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Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β‐catenin signaling cascades and reversal of epithelial–mesenchymal transition

et al. 2016

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Cardamonin (CD), an active chalconoid, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of CD for the treatment of triple negative breast cancer (TNBC) is unclear. This study aims to examine the cytotoxic effects of CD and investigate the underlying mechanism in human TNBC cells. The results show that CD exhibits cytotoxicity by inducing apoptosis and cell cycle arrest in TNBC cells via modulation of Bcl-2, Bax, cyt-C, cleaved caspase-3, and PARP. We find that CD significantly increases expression of the epithelial marker E-cadherin, while reciprocally decreasing expression of mesenchymal markers such as snail, slug, and vimentin in BT-549 cells. In parallel with epithelial-mesenchymal transition (EMT) reversal, CD down regulates invasion and migration of BT-549 cells. CD markedly reduces stability and nuclear translocation of β-catenin, accompanied with downregulation of β-catenin target genes. Using the TopFlash luciferase reporter assay, we reveal CD as a specific inhibitor of the Wnt3a-induced signaling. These results suggest the involvement of the Wnt/β-catenin signaling in the CD-induced EMT reversion of BT-549 cells. Notably, CD restores the glycogen synthase kinase-3β (GSK3β) activity, required for β-catenin destruction via the proteasome-mediated system, by inhibiting the phosphorylation of GSK3β by Akt. These occurrences ultimately lead to the blockage of EMT and the invasion of TNBC cells. Further antitumor activity of CD was tested in 4T1 (TNBC cells) induced tumor and it was found that CD significantly inhibited the tumor volume at dose of 5 mg/kg-treated mice. © 2016 BioFactors, 43(2):152-169, 2017.

show abstract

Dentatin isolated from Clausena excavata induces apoptosis in MCF-7 cells through the intrinsic pathway with involvement of NF-κB signalling and G0/G1 cell cycle arrest: A bioassay-guided approach

Cited by 46 publications

References 35 publications

Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)

Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)

Anticancer activity of a monobenzyltin complex C1 against MDA-MB-231 cells through induction of Apoptosis and inhibition of breast cancer stem cells

Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β‐catenin signaling cascades and reversal of epithelial–mesenchymal transition

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