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Anticancer Properties of Platinum Nanoparticles and Retinoic Acid: Combination Therapy for the Treatment of Human Neuroblastoma Cancer.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Sep 16; Vol. 21 (18). Date of Electronic Publication: 2020 Sep 16. - Publication Year :
- 2020
-
Abstract
- Neuroblastoma is the most common extracranial solid tumor in childhood. The different treatments available for neuroblastoma are challenged by high rates of resistance, recurrence, and progression, most notably in advanced cases and highly malignant tumors. Therefore, the development of more targeted therapies, which are biocompatible and without undesired side effects, is highly desirable. The mechanisms of actions of platinum nanoparticles (PtNPs) and retinoic acid (RA) in neuroblastoma have remained unclear. In this study, the anticancer effects of PtNPs and RA on neuroblastoma were assessed. We demonstrated that treatment of SH-SY5Y cells with the combination of PtNPs and RA resulted in improved anticancer effects. The anticancer effects of the two compounds were mediated by cytotoxicity, oxidative stress (OS), mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and apoptosis-associated networks. Cytotoxicity was confirmed by leakage of lactate dehydrogenase (LDH) and intracellular protease, and oxidative stress increased the level of reactive oxygen species (ROS), 4-hydroxynonenal (HNE), malondialdehyde (MDA), and nitric oxide (NO), and protein carbonyl content (PCC). The combination of PtNPs and RA caused mitochondrial dysfunction by decreasing the mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) content, number of mitochondria, and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Endoplasmic reticulum-mediated stress and apoptosis were confirmed by upregulation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), activating transcription factor 4 (ATF4), p53, Bax, and caspase-3 and down regulation of B-cell lymphoma 2 (BCl-2). PtNPs and RA induced apoptosis, and oxidative DNA damage was evident by the accumulation of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG). Finally, PtNPs and RA increased the differentiation and expression of differentiation markers. Differentiated SH-SY5Y cells pre-treated with PtNPs or RA or the combination of both were more sensitive to the cytotoxic effect of cisplatin than undifferentiated cells. To our knowledge, this is the first study to demonstrate the effect of the combination of PtNPs and RA in neuroblastoma cells. PtNPs may be a potential preconditioning or adjuvant compound in chemotherapeutic treatment. The results of this study provide a rationale for clinical evaluation of the combination of PtNPs and RA for the treatment of children suffering from high-risk neuroblastoma.
- Subjects :
- Antineoplastic Agents administration & dosage
Antineoplastic Agents chemical synthesis
Antioxidants metabolism
Apoptosis drug effects
Cell Differentiation drug effects
Cell Division drug effects
Cell Line, Tumor
Cisplatin pharmacology
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Drug Synergism
Endoplasmic Reticulum Stress drug effects
Humans
L-Lactate Dehydrogenase analysis
Membrane Potential, Mitochondrial drug effects
Metal Nanoparticles chemistry
Metal Nanoparticles toxicity
Neoplasm Proteins metabolism
Neuroblastoma pathology
Oxidative Stress drug effects
Peptide Hydrolases analysis
Platinum administration & dosage
Platinum toxicity
Tretinoin administration & dosage
beta Carotene pharmacology
Antineoplastic Agents pharmacology
Metal Nanoparticles therapeutic use
Neuroblastoma drug therapy
Platinum pharmacology
Tretinoin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32947930
- Full Text :
- https://doi.org/10.3390/ijms21186792