Induction of Apoptosis by Sinulariolide from Soft Coral through Mitochondrial-Related and p38MAPK Pathways on Human Bladder Carcinoma Cells

Neoh, Choo-Aun; Wang, Chia Hui; Din, Zhong-Hao; Su, Jui‐Hsin; Chen, Yu-Kuei; Tsai, Feng‐Jen; Weng, Shun-Hsiang; Wu, Yu-Jen

doi:10.3390/md10122893

Cited by 38 publications

(48 citation statements)

References 56 publications

(64 reference statements)

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“…Consistent with these studies, we found that CMT-3 effectively induced the oxidative stress state of cytoplasm and spontaneously induced apoptosis in HeLa cells (Fig. Cytochrome c from the mitochondria works in combination with caspase-9, apoptotic protease activating factor-1, and ATP to process procaspase-3 to cleave caspase-3 [30] and further cleave its substrate PARP, inducing characteristic apoptotic progress, such as chromatin condensation and DNA chromatin fragmentation [31]. On the one hand, elevated free ROS radicals may cause oxidative damage to mitochondrial DNA, proteins, and lipids, which results in the disruption of mitochondrial membrane potential [28,29].…”

Section: Discussionsupporting

confidence: 80%

Inhibitory impacts of chemically modified tetracycline-3 and underlying mechanism in human cervical cancer cells

Zhao

Xu²,

Yang³

et al. 2013

Anti-Cancer Drugs

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Chemically modified tetracyclines (CMTs) have been rationally designed from tetracyclines. The CMTs that show the antimicrobial properties are eliminated, whereas matrix metalloproteinase inhibitory properties are retained. Interestingly, CMT-3 (COL-3, by eliminating the dimethylamino, methyl, and hydroxyl functionalities on the basic tetracycline structure), one of the CMTs, has shown strong anticancer activity. In this study, we found that CMT-3 showed dose-dependent and time-dependent cytotoxicity in HeLa and Siha cells, two human cervical cancer cell lines. HeLa cells were more sensitive to CMT-3 compared with Siha cells. The antiproliferation potential of CMT-3 was associated with the mitochondrial apoptosis pathway, increasing reactive oxygen species level, and proapoptosis protein (e.g. caspase-3) expression, but decreasing antiapoptosis protein expression (e.g. Bcl-2). N-acetylcysteine (a reactive oxygen species inhibitor) and Z-LEHD-FMK significantly reduced or blocked the apoptosis event resulting from cytotoxic effect of CMT-3. CMT-3 also induced G0/G1 phase arrest with the reduction of cell cycle regulatory protein cyclin E and the translocation of NF-κB from the cytoplasm to the nucleus. Our findings provide the important foundation for further investigation of the underlying mechanism for the anticancer activity of CMT-3 and the potential application of CMT-3 as a new therapeutic candidate for clinical cervical cancer therapy.

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Section: Discussionsupporting

confidence: 80%

Inhibitory impacts of chemically modified tetracycline-3 and underlying mechanism in human cervical cancer cells

Zhao

Xu²,

Yang³

et al. 2013

Anti-Cancer Drugs

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“…It has previously been shown that sinulariolide induced apoptosis of TSGH cells [18]. A375 cells showed growth inhibition with sinulariolide treatment in a concentration-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…The mitochondria and cytosol fractions were separated using a mitochondria/cytosol fractionation kit (BioSource) by the methods described in our previous report [18]. …”

Section: 9 Mitochondria and Cytosol Fractionationmentioning

confidence: 99%

“…Sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis , has been shown to have various biological properties, including anti-microbial and anti-bladder cancer activities [18,19]. In the current investigation, the effects of sinulariolide on melanoma cells were evaluated in terms of cell viability, cell migration, and flow cytometric analysis.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic Investigation of the Sinulariolide-Treated Melanoma Cells A375: Effects on the Cell Apoptosis through Mitochondrial-Related Pathway and Activation of Caspase Cascade

Chiu

et al. 2013

Marine Drugs

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Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigated the effects of sinulariolide on A375 melanoma cell growth and protein expression. Sinulariolide suppressed the proliferation and migration of melanoma cells in a concentration-dependent manner and was found to induce both early and late apoptosis by flow cytometric analysis. Comparative proteomic analysis was conducted to investigate the effects of sinulariolide at the molecular level by comparison between the protein profiles of melanoma cells treated with sinulariolide and those without treatment. Two-dimensional gel electrophoresis (2-DE) master maps of control and treated A375 cells were generated by analysis with PDQuest software. Comparison between these maps showed up- and downregulation of 21 proteins, seven of which were upregulated and 14 were downregulated. The proteomics studies described here identify some proteins that are involved in mitochondrial dysfunction and apoptosis-associated proteins, including heat shock protein 60, heat shock protein beta-1, ubiquinol cytochrome c reductase complex core protein 1, isocitrate dehydrogenase (NAD) subunit alpha (down-regulated), and prohibitin (up-regulated), in A375 melanoma cells exposed to sinulariolide. Sinulariolide-induced apoptosis is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome c, and activation of Bax, Bad and caspase-3/-9, as well as suppression of p-Bad, Bcl-xL and Bcl-2. Taken together, our results show that sinulariolide-induced apoptosis might be related to activation of the caspase cascade and mitochondria dysfunction pathways. Our results suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human melanoma.

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“…Chemical compounds, such as diterpenoids, diterpenes, and prostanoids, isolated from marine soft corals, exert various biological activities, including antiproliferation, antimigratory, and antiapoptotic, on different cancer cell lines, such as prostate cancer cells, HCC cells, breast cancer cells, colon cancer cells, cervical cancer cells, oral squamous cells, bladder cancer cells, and melanoma cells [12,13,14,15,16,17]. …”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction

Lin

Wang

Chen

et al. 2016

IJMS

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Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on four hepatocellular carcinoma cell lines. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the results demonstrated that 11-epi-SA treatment showed more cytotoxic effect toward HA22T cells. Protein profiling of the 11-epi-SA-treated HA22T cells revealed substantial protein alterations associated with stress response and protein synthesis and folding, suggesting that the mitochondria and endoplasmic reticulum (ER) play roles in 11-epi-SA-initiated apoptosis. Moreover, 11-epi-SA activated caspase-dependent apoptotic cell death, suggesting that mitochondria-related apoptosis genes were involved in programmed cell death. The unfolded protein response signaling pathway-related proteins were also activated on 11-epi-SA treatment, and these changes were accompanied by the upregulated expression of growth arrest and DNA damage-inducible protein (GADD153) and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), the genes encoding transcription factors associated with growth arrest and apoptosis under prolonged ER stress. Two inhibitors, namely salubrinal (Sal) and SP600125, partially abrogated 11-epi-SA-related cell death, implying that the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)–activating transcription factor (ATF) 6–CHOP or the inositol-requiring enzyme 1 alpha (IRE1α)–c-Jun N-terminal kinase (JNK)–cJun signal pathway was activated after 11-epi-SA treatment. In general, these results suggest that 11-epi-SA exerts cytotoxic effects on HA22T cells through mitochondrial dysfunction and ER stress cell death pathways.

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Induction of Apoptosis by Sinulariolide from Soft Coral through Mitochondrial-Related and p38MAPK Pathways on Human Bladder Carcinoma Cells

Cited by 38 publications

References 56 publications

Inhibitory impacts of chemically modified tetracycline-3 and underlying mechanism in human cervical cancer cells

Inhibitory impacts of chemically modified tetracycline-3 and underlying mechanism in human cervical cancer cells

Proteomic Investigation of the Sinulariolide-Treated Melanoma Cells A375: Effects on the Cell Apoptosis through Mitochondrial-Related Pathway and Activation of Caspase Cascade

Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction

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