Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression

Chen, Yu Cheng; Lu, Mei; El-Shazly, Mohamed; Lai, Kuei Hung; Wu, Tung Ying; Hsu, Yu Ming; Lee, Yi Lun; Liu, Yi Chang

doi:10.3390/md16060212

Cited by 24 publications

(67 citation statements)

References 60 publications

(71 reference statements)

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“…After 24 h, 13-AC resulted in a concentration-dependent (0, 2.5, 5, and 10 μg/mL) increase of the population of cells with disrupted mitochondrial membrane potential from 4% to 95% ( Figure 4 A). The generation of the intracellular ROS by 13-AC treatment was determined with a carboxyl derivative of fluorescein, carboxy-H 2 DCFDA dye using flow cytometric analysis [ 25 ]. As shown in Figure 4 B, the treatment with 13-AC (10 μg/mL) for 0.5, 1, 3, and 6 h resulted in 3.32-, 3.96-, 4.98-, and 3.05-fold increases in ROS levels, respectively, as compared with the mean fluorescence index (MFI) of the control.…”

Section: Resultsmentioning

confidence: 99%

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13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity against Oral Cancer Cells through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts

et al. 2020

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13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.

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Section: Resultsmentioning

confidence: 99%

“…In nude mice, the xenograft animal model was established following the reported literature [24,25]. The National Laboratory Animal and Research Center (Taipei, Taiwan) was the supplier for the six-week-old male immunodeficient athymic mice.…”

Section: Animal Materials and Xenograft Animal Model With Human Oral Cmentioning

confidence: 99%

13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity against Oral Cancer Cells through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts

et al. 2020

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“…As mentioned above, both high [12] and low (the current study) concentrations of WFA induced ROS. Moreover, ROS can regulate MAPK signaling [45], which is associated with tumor cell invasion [46]. Cytotoxic concentration of WFA induces apoptosis by phosphorylating p38 and ERK1/2 in leukemic [47] and glioblastomas cells [48], respectively.…”

Section: Mapk Changes In Wfa-treated Oral Cancer Cellsmentioning

confidence: 99%

Low Concentration of Withaferin a Inhibits Oxidative Stress-Mediated Migration and Invasion in Oral Cancer Cells

Tang

Ou‐Yang

et al. 2020

Biomolecules

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Withaferin A (WFA) has been reported to inhibit cancer cell proliferation based on high cytotoxic concentrations. However, the low cytotoxic effect of WFA in regulating cancer cell migration is rarely investigated. The purpose of this study is to investigate the changes in migration and mechanisms of oral cancer Ca9-22 cells after low concentrations of WFA treatment. WFA under 0.5 μM at 24 h treatment shows no cytotoxicity to oral cancer Ca9-22 cells (~95% viability). Under this condition, WFA triggers reactive oxygen species (ROS) production and inhibits 2D (wound healing) and 3D cell migration (transwell) and Matrigel invasion. Mechanically, WFA inhibits matrix metalloproteinase (MMP)-2 and MMP-9 activities but induces mRNA expression for a group of antioxidant genes, such as nuclear factor, erythroid 2-like 2 (NFE2L2), heme oxygenase 1 (HMOX1), glutathione-disulfide reductase (GSR), and NAD(P)H quinone dehydrogenase 1 (NQO1)) in Ca9-22 cells. Moreover, WFA induces mild phosphorylation of the mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 expression. All WFA-induced changes were suppressed by the presence of ROS scavenger N-acetylcysteine (NAC). Therefore, these results suggest that low concentration of WFA retains potent ROS-mediated anti-migration and -invasion abilities for oral cancer cells.

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“…Heteronemin, the most plentiful secondary metabolite in the sponge Hippospongia sp., shows effective cytotoxic activity against different cancer cells. It increases the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells [16]. Furthermore, heteronemin-induced production of ROS from the mitochondria and apoptosis can be suppressed [16] by the ROS scavenger, N-acetyl cysteine (NAC) [17].…”

Section: Introductionmentioning

confidence: 99%

“…It increases the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells [16]. Furthermore, heteronemin-induced production of ROS from the mitochondria and apoptosis can be suppressed [16] by the ROS scavenger, N-acetyl cysteine (NAC) [17]. Heteronemin has been shown to increase talin expression and the accumulation of phosphorylated talin in Molt4 cells, but it is only able to increase phosphorylated talin in human embryonic kidney 293 (HEK293) cells [16].…”

Section: Introductionmentioning

confidence: 99%

Heteronemin Induces Anti-Proliferation in Cholangiocarcinoma Cells via Inhibiting TGF-β Pathway

Lin

Tey

et al. 2018

Marine Drugs

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A marine sesterterpenoid-type natural product, heteronemin, retains anticancer effects. In the current study, we investigate the antitumor mechanism of heteronemin in cholangiocarcinoma cells and further explore its molecular targets. Initially, heteronemin exhibited potent cytotoxic effects against cholangiocarcinoma HuccT1 and SSP-25 cells. In vitro, heteronemin altered the abilities of cell adhesion and cell migration in HuccT1 and SSP-25 cell lines. It repressed messenger ribonucleic acid (mRNA) expression levels of transforming growth factor (TGF)-β, mothers against decapentaplegic homolog (SMAD) and Myc, whose protein products play important roles in regulating cell growth, angiogenesis, and metastasis. In addition, heteronemin altered several signaling pathways. The results indicate that heteronemin was able to modulate cell adhesion, the expression of extracellular matrix (ECM) receptors, the TGF-β pathway, cell motility, the membrane integration, metastasis response, matrix metalloproteinase (MMP) remodeling, the regulation of metabolism, sprouting angiogenesis, transcription factors, and vasculogenesis in cholangiocarcinoma cell lines. The results also suggest that it activated multiple signal transduction pathways to induce an anti-proliferation effect and anti-metastasis in cholangiocarcinoma. In conclusion, heteronemin may be used as a potential medicine for anticancer therapy.

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Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression

Cited by 24 publications

References 60 publications

13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity against Oral Cancer Cells through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts

13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity against Oral Cancer Cells through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts

Low Concentration of Withaferin a Inhibits Oxidative Stress-Mediated Migration and Invasion in Oral Cancer Cells

Heteronemin Induces Anti-Proliferation in Cholangiocarcinoma Cells via Inhibiting TGF-β Pathway

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