scholarly journals Altered Ca2+-Homeostasis of Cisplatin-Treated and Low Level Resistant Non-Small-Cell and Small-Cell Lung Cancer Cells

2009 ◽  
Vol 31 (4) ◽  
pp. 301-315
Author(s):  
Kathrin Schrödl ◽  
Hamza Oelmez ◽  
Martin Edelmann ◽  
Rudolf Maria Huber ◽  
Albrecht Bergner
Keyword(s):  
Lung Cancer ◽  
Endoplasmic Reticulum ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cisplatin Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Low Level ◽  
Level Resistance

Background: Chemotherapy often leads to encouraging responses in lung cancer. But, in the course of the treatment, resistance to chemotherapy ultimately limits the life expectancy of the patient. We aimed at investigating if treatment with cisplatin alters the intracellular Ca2+-homeostasis of lung cancer cells and how this may be related to cisplatin resistance.Methods: The squamous cell lung carcinoma cell line EPLC M1 and the small cell lung cancer cell line H1339 were exposed to cisplatin analogue to the in vivo pharmacokinetics. Changes in the cytoplasmic Ca2+-concentration ([Ca2+]c) were recorded using fluorescence microscopy. Protein expression was quantified using immuno-fluorescence and Western Blot analysis. Changes in gene expression were accomplished by small-interfering (si) RNA techniques.Results: Four “cycles” of cisplatin led to low level resistance in EPLC and H1339 cells. In the low level resistant cell clones, the Ca2+-content of the endoplasmic reticulum (ER) was decreased. In low level resistant EPLC cells, this was correlated with an increased expression of the inositol-1,4,5-trisphosphate receptor (IP3R). Inhibiting the increased expression of IP3R using siRNA, the low level resistance could be reversed. In low level resistant H1339 cells, the decreased Ca2+-content of the ER was correlated with a decreased expression of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA). Decreasing the expression of SERCA in naïve H1339 cells resulted in low level cisplatin resistance.Conclusion: We conclude that cisplatin therapy leads to a decreased Ca2+-content of the ER thereby inducing low level resistance. This is caused by upregulation of the IP3R in EPLC and decreased expression of SERCA in H1339 cells.

Novel pathways involved in cisplatin resistance identified by a proteomics approach in non‐small‐cell lung cancer cells

2018 ◽  
Vol 234 (6) ◽  
pp. 9077-9092 ◽  
Author(s):  
Maria Rita Milone ◽  
Rita Lombardi ◽  
Maria Serena Roca ◽  
Francesca Bruzzese ◽  
Laura Addi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Cisplatin Resistance ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Small Cell Lung ◽  
Proteomics Approach

scholarly journals Encapsulation of Nedaplatin in Novel PEGylated Liposomes Increases Its Cytotoxicity and Genotoxicity against A549 and U2OS Human Cancer Cells

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 863 ◽  
Author(s):  
Salma El-Shafie ◽  
Sherif Ashraf Fahmy ◽  
Laila Ziko ◽  
Nada Elzahed ◽  
Tamer Shoeib ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung

Following the discovery of cisplatin over 50 years ago, platinum-based drugs have been a widely used and effective form of cancer therapy, primarily causing cell death by inducing DNA damage and triggering apoptosis. However, the dose-limiting toxicity of these drugs has led to the development of second and third generation platinum-based drugs that maintain the cytotoxicity of cisplatin but have a more acceptable side-effect profile. In addition to the creation of new analogs, tumor delivery systems such as liposome encapsulated platinum drugs have been developed and are currently in clinical trials. In this study, we have created the first PEGylated liposomal form of nedaplatin using thin film hydration. Nedaplatin, the main focus of this study, has been exclusively used in Japan for the treatment of non-small cell lung cancer, head and neck, esophageal, bladder, ovarian and cervical cancer. Here, we investigate the cytotoxic and genotoxic effects of free and liposomal nedaplatin on the human non-small cell lung cancer cell line A549 and human osteosarcoma cell line U2OS. We use a variety of assays including ICP MS and the highly sensitive histone H2AX assay to assess drug internalization and to quantify DNA damage induction. Strikingly, we show that by encapsulating nedaplatin in PEGylated liposomes, the platinum uptake cytotoxicity and genotoxicity of nedaplatin was significantly enhanced in both cancer cell lines. Moreover, the enhanced platinum uptake as well as the cytotoxic/antiproliferative effect of liposomal nedaplatin appears to be selective to cancer cells as it was not observed on two noncancer cell lines. This is the first study to develop PEGylated liposomal nedaplatin and to demonstrate the superior cell delivery potential of this product.

scholarly journals Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

Cancers ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 126 ◽  
Author(s):  
Christophe Deben ◽  
Vanessa Deschoolmeester ◽  
Jorrit De Waele ◽  
Julie Jacobs ◽  
Jolien Van den Bossche ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Cisplatin Resistance ◽  
Small Cell ◽  
Mutant P53 ◽  
Small Cell Lung ◽  
Hypoxic Conditions

The compound APR-246 (PRIMA-1MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

Inhibition of microRNA-196a might reverse cisplatin resistance of A549/DDP non-small-cell lung cancer cell line

Tumor Biology ◽  
2015 ◽  
Vol 37 (2) ◽  
pp. 2387-2394 ◽  
Author(s):  
Jian-Huang Li ◽  
Ning Luo ◽  
Mei-Zuo Zhong ◽  
Zhi-Qiang Xiao ◽  
Jian-Xin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Cisplatin Resistance ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung
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