Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

Tyler, Andreas; Johansson, Anders; Karlsson, Terese; Gudey, Shyam Kumar; Brännström, Thomas; Grankvist, Kjell; Behnam‐Motlagh, Parviz

doi:10.1016/j.yexcr.2015.05.012

Cited by 40 publications

(27 citation statements)

References 44 publications

(64 reference statements)

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“…Cisplatin [cis-diamminedichloroplatinum (CDDP)]-based combination chemotherapy has markedly improved the survival rate of SCLC patients (3), However, the median survival time of SCLC patients with limited and advanced stage are still less than 2 years, and the overall 5-year survival rate of SCLC patients remains 5-10% owing to acquired multidrug resistance (MDR) and intolerable toxicity (4). It has been found that apoptosis blockade is one of the most important mechanisms by which cancer cells escape from the cytotoxicity of cisplatin, leading to MDR (5). Therefore, it is of great significance for cancer treatments to explore the mechanisms of apoptotic resistance after cisplatin stimulation and to accelerate apoptosis in tumor cells in efficient ways.…”

Section: Introductionmentioning

confidence: 99%

Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway

Wang

Weng

et al. 2016

Oncology Reports

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Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype and accounts for more than 15% of all lung cancer cases. Cisplatin [cis-diamminedichloroplatinum (CDDP)]-based combination chemotherapy is the cornerstone for all stages of SCLC. However, acquired multidrug resistance (MDR) and intolerable toxicities lead to a high mortality rate in SCLC patients. Gallic acid [3,4,5-trihydroxybenzoic acid (GA)] is a natural botanic phenolic compound which can induce cell apoptosis in several types of cancers. In the present study, we aimed to explore the anticancer effects of GA on human SCLC H446 cells and its promotive effects on the anticancer activities of cisplatin. The viability of the H446 cells was analyzed by MTT assay. Morphological changes in the H446 cells were observed under an inverted microscope. Apoptosis induction was determined by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The level of reactive oxygen species (ROS) was assessed by 2'7'-dichlorofluorescein diacetate (DCFH‑DA), mitochondrial membrane potential (MMP) by JC-1, and western blotting was used to examine the expression of mitochondrial apoptosis-related proteins. The results showed that both GA and cisplatin changed the morphology, inhibited the growth and induced apoptosis in the H446 cells by inducing generation of ROS, disruption of MMP, downregulation of XIAP expression, and upregulation of Bax, Apaf-1, DIABLO and p53 expression. More importantly, GA combined with cisplatin exhibited synergistic effects on inducing of these pro-apoptotic mediators and modulating the activation of apoptosis-related molecules. However, inhibition of the generation of ROS by N-acetyl-l-cysteine (NAC), a specific ROS inhibitor, reversed the cell apoptosis induced by cisplatin combined with GA. In conclusion, the results from the present study revealed that GA exhibited an anticancer effect on human SCLC H446 cells and enhanced the antitumor activities of cisplatin via the ROS-dependent mitochondrial apoptotic pathway.

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Section: Introductionmentioning

confidence: 99%

Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway

Wang

Weng

et al. 2016

Oncology Reports

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“…PPMP treatment substantially sensitizes cells to cisplatin cytotoxicity [39]. These data suggest that therapies targeting glucosylceramide synthase activity or Gb3 receptors may ameliorate acquired cisplatin drug resistance in lung cancer cells.…”

Section: Ceramide As Potential Lung Cancer Treatment Strategy and Monmentioning

confidence: 77%

“…Further evidence shows that during cigarette smoking, EGFR is favorably co-localized in ceramideenriched regions of the plasma membrane, suggesting that nSMase2/ceramide plays a role in the aberrant EGFR activation, leading to augmented tumorigenic signaling and drug resistance [36]. Increased ceramide also triggers multidrug-resistant gene expression and synthesis of the pro-survival S1P and cell surface glycosphingolipids Gb3, which provide additional mechanisms for acquired drug resistance [8,28,[37][38][39].…”

Section: Ceramide and Related Enzymes In Lung Cancer Pathologymentioning

confidence: 99%

Sphingolipid in Lung Cancer Pathogenesis and Therapy

Bieberich¹,

Wang²

2017

A Global Scientific Vision - Prevention, Diagnosis, and Treatment of Lung Cancer

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Recent genomic research has ranked sphingolipid metabolism as the top dysregulated pathways in lung cancer, demonstrating that these lipids and their metabolic enzymes play key roles in lung cancer pathogenesis. Hence, sphingolipid metabolism has become a forefront in lung cancer research. However, the function of the diverse sphingolipids and their metabolic enzymes and the underlying mechanism in lung cancer are still unclear. In this chapter, we will focus on ceramide and sphingosine-1-phosphate (S1P), the best characterized sphingolipids so far, to summarize the most recent studies and highlight the essential role of sphingolipids in lung cancer pathology, diagnosis, and treatment.

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“…Therefore, the repair ability of DNA repair genes is closely related to the effectiveness of lung cancer chemotherapy. High repair ability induces chemotherapy resistance formation and causes chemotherapy failure [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance

et al. 2016

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BackgroundSurgery combined with chemotherapy is an important therapy for non-small cell lung cancer (NSCLC). However, chemotherapy drug resistance seriously hinders the curative effect. Studies show that DNA repair genes ERCC1 and BRCA1 are associated with NSCLC chemotherapy, but their expression and mechanism in NSCLC chemotherapy drug-resistant cells has not been elucidated.Material/MethodsNSCLC cell line A549 and drug resistance cell line A549/DDP were cultured. Real-time PCR and Western blot analyses were used to detect ERCC1 and BRCA1 mRNA expression. A549/DDP cells were randomly divided into 3 groups: the control group; the siRNA-negative control group (scramble group); and the siRNA ERCC1 and BRCA1siRNA transfection group. Real-time PCR and Western blot analyses were used to determine ERCC1 and BRCA1 mRNA and protein expression. MTT was used to detect cell proliferation activity. Caspase 3 activity was tested by use of a kit. Western blot analysis was performed to detect PI3K, AKT, phosphorylated PI3K, and phosphorylated AKT protein expression.ResultsERCC1 and BRCA1 were overexpressed in A549/DDP compared with A549 (P<0.05). ERCC1 and BRCA1siRNA transfection can significantly reduce ERCC1 and BRCA1 mRNA and protein expression (P<0.05). Downregulating ERCC1 and BRCA1 expression obviously inhibited cell proliferation and increased caspase 3 activity (P<0.05). Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P<0.05).ConclusionsERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway.

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Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

Cited by 40 publications

References 44 publications

Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway

Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway

Sphingolipid in Lung Cancer Pathogenesis and Therapy

DNA Repair Genes ERCC1 and BRCA1 Expression in Non-Small Cell Lung Cancer Chemotherapy Drug Resistance

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