Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells

Ansari, Shariq; Sharma, Ashwini Kumar; Soni, Himanshu; Ali, Doaa M.; Tews, Björn; König, Rainer; Eibl, Hansjörg; Berger, Martin R.

doi:10.1038/s41419-018-0342-2

Cited by 32 publications

(19 citation statements)

References 51 publications

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“…These results further suggest that PT induces ER stress-mediated apoptosis in ESCC cells. MMP is essential for the generation of ATP to modulate physiological activity, and a collapse of MMP is an indicator of cellular integrity in the early stages of apoptosis [34,35]. PT treatment increases the percentage of depolarized cells, indicating a loss of MMP in PT-induced apoptosis ( Figure 5A).…”

Section: Discussionmentioning

confidence: 99%

Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

Yoon

Lee

Kwak

et al. 2019

Forests

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Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in East Asia and is the seventh leading cause of cancer deaths. Podophyllotoxin (PT), a cyclolignan isolated from podophyllum peltatum, exhibits anti-cancer effects at the cellular level. This study investigated the underlying mechanism of anti-cancer effects induced by PT in ESCC cells. Exposure to increasing concentrations of PT led to a significant decrease in the growth and anchorage-independent colony numbers of ESCC cells. PT showed high anticancer efficacy against a panel of four types of ESCC cells, including KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510 by IC50 at values ranges from 0.17 to 0.3 μM. We also found that PT treatment induced G2/M phase arrest in the cell cycle and accumulation of the sub-G1 population, as well as apoptosis. Exposure to PT triggered a significant synthesis of reactive oxygen species (ROS), a loss of mitochondrial membrane potential (MMP), and activation of various caspases. Furthermore, PT increased the levels of phosphorylated c-Jun N-terminal kinase (JNK), p38, and the expression of Endoplasmic reticulum (ER) stress marker proteins via ROS generation. An increase in the level of pro-apoptotic proteins and a reduction in the anti-apoptotic protein level induced ESCC cell death via the loss of MMP. Additionally, the release of cytochrome c into the cytosol with Apaf-1 induced the activation of multi-caspases. In conclusion, our results revealed that PT resulted in apoptosis of ESCC cells by modulating ROS-mediated mitochondrial and ER stress-dependent mechanisms. Therefore, PT is a promising therapeutic candidate as an anti-cancer drug against ESCC for clinical use.

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Section: Discussionmentioning

confidence: 99%

Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

Yoon

Lee

Kwak

et al. 2019

Forests

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“…A large number of studies on various medicinal herbs have shown that they may induce ROS-mediated apoptosis in OSCC cells. For example, erufosine is able to induce ROS in OSCC cell lines and the loss of mitochondrial membrane potential [ 42 ]. β-lapachone produces reactive oxygen species-mediated apoptosis in human OSCC cells [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model

Chen

Liu

et al. 2018

Marine Drugs

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Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics.

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“…Perifosine and also the ether lipid edelfosine can induce autophagy by evoking an ER stress response, as demonstrated by a two-to threefold increased expression of the apoptotic transcription factor CHOP (C/EBP homologous protein)/ GADD153 (growth arrest and DNA damage inducible gene 153) in human hepatoblastoma HepG2 cells, but not in human glioblastoma U-87 MG cells. It should be noted that miltefosine was devoid of this ER stress inducing effect (Rios-Marco et al, 2015), but erufosine was able to strongly cause ER stress ( (Ansari et al, 2018a) and see below).…”

Section: Perifosinementioning

confidence: 99%

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

2020

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Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e. protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/ mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second-and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy in vitro and in vivo. mTOR is a downstream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.

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Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells

Cited by 32 publications

References 51 publications

Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

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