Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS

Asby, Daniel; Radigois, M. G.; Wilson, Dharyl C.; Cuda, Francesco; Chai, Christina L. L.; Chen, A.; Bienemann, Alison; Light, Mark E.; Harrowven, David C.; Tavassoli, Ali

doi:10.1039/c6ob01591c

Cited by 10 publications

(7 citation statements)

References 27 publications

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“…Recently, ROS based drug advancement has become major attribute for cancer management irrespective of its heterogeneity and genotype. [41][42][43] In this study, we have elucidated the functional link between ROS generation and cytocidal effect of Brv-A by using NAC. Our data demonstrated that Brv-A significantly inhibited viability of both triple positive and triple negative breast cancer cell types, however, only triple positive MCF-7 cells were used for further mechanistic study.…”

Section: Discussionmentioning

confidence: 99%

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

Saleem

Nisar

Alshwmi

et al. 2020

OTT

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Breast cancer is the most common malignancy among women across the globe. Despite concerted efforts to improve the prevailing treatment modalities, the overall prognosis of breast cancer remains unsatisfactory. Recently, antiproliferative activity of Brevilin A (Brv-A), a sesquiterpene lactone compound of Centipeda minima, has been unveiled in various cancer types. Here, we have explored anticancer activity of Brv-A in MCF-7 breast carcinoma cells by targeting various pathways. Materials and Methods: Cell proliferation rate was determined by CCK-8 and clonogenic assay. Cellular morphological changes were observed under phase contrast microscope while calcein-AM and PI was used for live/dead assay. Cell cycle assay was performed by flow cytometry. Apoptotic cell percentage was determined by Hoechst 33258 staining and flow cytometric analysis. ROS generation and mitochondrial membrane potential were measured using commercially available kits while protein expression was measured by Western blotting. Results: In our study, Brv-A exerted antiproliferative effect through mitotic arrest at G 2 /M phase of cell cycle and induced apoptosis in MCF-7 cells in a dose-dependent manner. Induction of apoptosis by Brv-A was found to be associated with ROS generation by targeting NOX2 and NOX3, mitochondrial dysfunction (MMP dissipation and Bcl-2 family proteins modulation), DNA fragmentation, JNK and p38 MAPK activation, endoplasmic reticulum (ER) stress by increasing Bip/GRP78, ATF4 and CHOP protein expressions and inhibition of STAT3 activation via decreased phosphorylation of JAK2 and SRC. Pretreatment of NAC, a ROS scavenger, partially reversed the aforesaid cellular events indicating ROS generation as the primary event to modulate cellular targets for induction of apoptosis. Besides, Brv-A has also been documented for inhibition of cell migration via decrease in COX-2 and MMP-2 expression. Conclusion: Taken together, Brv-A induces G 2 /M phase arrest, ROS-dependent apoptosis, ER stress, mitochondrial dysfunction and inhibits STAT3 activation in MCF-7 cells signifying it to be one of the potential anticancer therapeutics in future.

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Section: Discussionmentioning

confidence: 99%

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

Saleem

Nisar

Alshwmi

et al. 2020

OTT

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“…Exploring new novel strategies for the effective treatment of cancer cells are therefore paramount. ROS-based drug development for effective treatment of cancer has emerged as a new paradigm in recent years 18, 33, 34 . We have previously showed that ALT, a sesquiterpene lactone compound induces ROS-mediated mitochondrial apoptosis in U87 glioblastoma and HepG2 liver cancer cells 21, 25 , however, the molecular targets and in-depth mechanism of ALT remains largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…At low level, ROS act as signaling molecules and play a vital role in various biological processes including cell survival, proliferation, differentiation and gene expression, at higher level however; ROS exert oxidative stress and induce cell death through various signaling pathways 15 . Killing cancer cells by exploiting this biochemical vulnerability of cancer cells with ROS-targeting phytochemicals has been shown to be feasible in various in vitro and in vivo experimental models 16, 18–20 . ROS-targeted anticancer drug development strategy holds the promise to set the cancer on the road to ruin as it can be applied more broadly against various human cancers of multiple origins irrespective of their genotype and are less likely to suffer from drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress

Maryam

Mehmood

Zhang

et al. 2017

Sci Rep

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Alantolactone (ALT), a sesquiterpene lactone component of Inula helenium, has been reported to exert anticancer activity in various cancers. However, the cellular targets and underlying mechanism of anticancer activity of ALT in various cancers including lung cancer has not been fully defined. In the present study, we found that ALT effectively inhibits proliferation and triggers oxidative stress mediated-apoptosis in A549 lung adenocarcinoma cells by inducing ER stress and mitochondrial dysfunction. This ALT-mediated apoptosis was inhibited by NAC while diamide potentiated it. Moreover, ALT effectively suppressed both constitutive and inducible STAT3 activation, inhibited its translocation into nucleus and decreased its DNA binding activity. Further mechanistic study revealed that ALT abrogated STAT3 activation by promoting STAT3 glutathionylation. ROS scavenger NAC reverted ALT-mediated STAT3 glutathionylation and inhibition of STAT3 phosphorylation. Finally, ALT enhanced chemosensitivity of A549 cells to doxorubicin and reversed doxorubicin resistance in A549/DR cells by inhibiting STAT3 activation and P-glycoprotein expression and increasing intracellular accumulation of doxorubicin. Suppression of STAT3 activation by targeting ROS metabolism with ALT thus discloses a previously unrecognized mechanism underlying the biological activity of ALT. Taken together; ALT induces oxidative stress-dependent apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in A549 lung cancer cells. These findings provide an in-depth insight into the molecular mechanism of ALT in the treatment of lung cancer.

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“…Indeed, induction of cell death in cancer cells by exposing them to an ROS-inducing phytochemical has been shown to be feasible in various in vitro cell culture studies and in vivo animal models. 17 – 19 Unlike prevailing chemotherapeutics, an ROS-based drug development strategy holds the promise to kill cancer cells of multiple origins more effectively, irrespective of their genotype and heterogeneity. 4 Among various classes of bioactive phytochemicals, sesquiterpene lactones have been reported to be the most potent ROS inducers.…”

Section: Discussionmentioning

confidence: 99%

Brevilin A promotes oxidative stress and induces mitochondrial apoptosis in U87 glioblastoma cells

Wang

Cui

et al. 2018

OTT

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BackgroundSesquiterpene lactones are plant-derived, natural, bioactive molecules often used against inflammatory diseases in traditional Chinese medicines. Recently, sesquiterpene lactones have been reported to exhibit potent anticancer activity. In the present study, we have investigated the anticancer activity of Brevilin A, a sesquiterpene lactone component of Centipeda minima, against U87 glioblastoma cells.Materials and methodsThe cell proliferation was determined by MTT assay. Cell morphological changes were observed by phase-contrast microscopy. Flow cytometry was used to measure apoptosis. Glutathione (GSH), ROS generation, and mitochondrial membrane potential were measured using commercially available kits. The expression of proteins was measured by Western blotting analysis.ResultsBrevilin A inhibited the proliferation of, and induced severe morphological changes and apoptotic cell death in, U87 glioblastoma cells in a dose-dependent manner. Further mechanistic study revealed that Brevilin A induces oxidative stress, as evident from ROS generation, GSH depletion, and increased phosphorylation of stress-activated proteins p38 and JNK. Furthermore, Brevilin A bcl-xl/bak ratio, decreased mitochondrial membrane potential and induced cytochrome c release from mitochondria into cytosol in a dose-dependent manner. Finally, Brevilin A decreased the expression of Xiap and increased the expression of cleaved forms of caspase-9 and -3 and PARP in a dose-dependent manner.ConclusionCollective findings demonstrated that Brevilin A is a potent, anticancer, bioactive molecule and it effectively induces apoptosis in U87 glioblastoma cells, which is associated with induction of oxidative stress and mitochondrial dysfunction.

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Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS

Abstract: A synthetic analogue of the marine natural product cribrostatin 6 is synthesized that selectively triggers apoptosis in cancer cells via elevation of intracellular ROS.

Cited by 10 publications

References 27 publications

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress

Brevilin A promotes oxidative stress and induces mitochondrial apoptosis in U87 glioblastoma cells

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