Examining impacts of ceranib-2 on the proliferation, morphology and ultrastructure of human breast cancer cells

Vejselova, Djanan; Kutlu, Hatice Mehtap; Kuş, Gökhan

doi:10.1007/s10616-016-9997-7

Cited by 16 publications

(10 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The hallmarks of apoptosis, which are cell shrinkage, membrane blebbing, chromatin condensation, nuclear fragmentation and mitochondrial swelling were detected via TEM in H460 cells. Further experiments by TEM showed that DU145, LNCaP and MCF-7 cells had similar morphological changes after ceranib-2 treatment (Kus et al 2015;Vethakanraj et al 2015;Vejselova et al 2016). Also vacuolization occurred in H460 cells after ceranib-2 application for 24 h. Ceramides are known to be important regulators of the crosstalk between apoptosis and autophagy (Gonzalez-Polo et al 2005;Young et al 2013).…”

Section: Discussionmentioning

confidence: 93%

The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro

2017

View full text Add to dashboard Cite

Ceramide is found to be involved in inhibition of cell division and induction of apoptosis in certain tumour cells. Ceranib-2 is an agent that increases ceramide levels by inhibiting ceramidase in cancer cells. Therefore, we aimed to investigate the effects of ceranib-2 on cell survival, apoptosis and interaction with carboplatin in human non-small cell lung cancer cells. The cytotoxic effect of ceranib-2 (1-100 µM) was determined by MTT assay in human lung adenocarcinoma (A549) and large cell lung carcinoma (H460) cells. Carboplatin (1-100 µM) and lung bronchial epithelial cells (BEAS-2B) were used as positive controls. Morphological and ultrastructural changes were analysed by light microscope and TEM. Apoptotic/necrotic cell death and acid ceramidase activity were analysed by ELISA. Combination effects of ceranib-2 and carboplatin were investigated by MTT. The expression levels of CASP3, CASP9, BAX and BCL-2 were examined by qRT-PCR. The IC of ceranib-2 was determined as 22 μM in A549 cells and 8 μM in H460 cells for 24 h. Morphological changes and induction of DNA fragmentation have revealed apoptotic effects of ceranib-2 in both cell lines. Ceranib-2 and carboplatin has shown synergism in combined treatment at 10 and 25 μM doses in H460 cells for 24 h. Ceranib-2 inhibited acid ceramidase activity by 44% at 25 µM in H460 cells. Finally, CASP3, CASP9 and BAX expressions were increased while BCL-2 expression was reduced in both cells. Our results obtained some preliminary results about the cytotoxic and apoptotic effects of ceranib-2 for the first time in NSCLC cell lines.

show abstract

Section: Discussionmentioning

confidence: 93%

The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro

2017

View full text Add to dashboard Cite

show abstract

“…Several studies have reported that ceramide is intimately involved in cancer pathogenesis. Alterations in its metabolism are involved in regulation of cancer initiation, progression, and/or response to chemotherapeutic agents and radiation [ 16 , 32 , 33 ]. However, the clinical relevance of ceramide levels in patients with breast cancer remains unclear, due to lack of accurate measurement of ceramides in human patients.…”

Section: Discussionmentioning

confidence: 99%

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

et al. 2018

View full text Add to dashboard Cite

Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients.

show abstract

“…showed in 2016 that Ceranib-2, a small molecule acid ceramidase inhibitor, decreased viability of MCF7 cells in a dose and time dependent manner. The authors suggested that this effect was mediated by the mitochondrial apoptosis pathway through modulation of the mitochondrial membrane potential (Vejselova et al, 2016). …”

Section: Acid Ceramidase (Asah1)mentioning

confidence: 99%

Ceramidases, roles in sphingolipid metabolism and in health and disease

Coant

Sakamoto

Mao

et al. 2017

Advances in Biological Regulation

200

146

View full text Add to dashboard Cite

Over the past three decades, extensive research has been able to determine the biologic functions for the main bioactive sphingolipids, namely ceramide, sphingosine, and sphingosine 1-phosphate (S1P)(Hannun, 1996; Hannun et al., 1986; Okazaki et al., 1989). These studies have managed to define the metabolism, regulation, and function of these bioactive sphingolipids. This emerging body of literature has also implicated bioactive sphingolipids, particularly S1P and ceramide, as key regulators of cellular homeostasis. Ceramidases have the important role of cleaving fatty acid from ceramide and producing sphingosine, thereby controlling the interconversion of these two lipids. Thus far, five human ceramidases encoded by five different genes have been identified: acid ceramidase (AC), neutral ceramidase (NC), alkaline ceramidase 1 (ACER1), alkaline ceramidase 2 (ACER2), and alkaline ceramidase 3 (ACER3). These ceramidases are classified according to their optimal pH for catalytic activity. AC, which is localized to the lysosomal compartment, has been associated with Farber’s disease and is involved in the regulation of cell viability. Neutral ceramidase, which is localized to the plasma membrane and primarily expressed in the small intestine and colon, is involved in digestion, and has been implicated in colon carcinogenesis. ACER1 which can be found in the endoplasmic reticulum and is highly expressed in the skin, plays an important role in keratinocyte differentiation. ACER2, localized to the Golgi complex and highly expressed in the placenta, is involved in programed cell death in response to DNA damage. ACER3, also localized to the endoplasmic reticulum and the Golgi complex, is ubiquitously expressed, and is involved in motor coordination-associated Purkinje cell degeneration. This review seeks to consolidate the current knowledge regarding these key cellular players..

show abstract

Examining impacts of ceranib-2 on the proliferation, morphology and ultrastructure of human breast cancer cells

Cited by 16 publications

References 40 publications

The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro

The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

Ceramidases, roles in sphingolipid metabolism and in health and disease

Contact Info

Product

Resources

About