Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups
| Autor: | M. Cristina Kenney, Nitin Udar, Steven D. Chang, Gregory Yung, Marilyn Chwa, Shari R. Atilano, Sina Abedi, Kunal Thaker, Kevin Schneider, Daniela A. Bota |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mitochondrial DNA
Cybrids Population lcsh:Medicine Mitochondrion Medical and Health Sciences General Biochemistry Genetics and Molecular Biology Haplogroup 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Lactate dehydrogenase Gene expression medicine Genetics education 030304 developmental biology Cisplatin Pharmacology 0303 health sciences education.field_of_study General Neuroscience lcsh:R General Medicine Cell Biology Genomics Biological Sciences Molecular biology Mitochondria Ophthalmology Anticancer chemistry Oncology 030220 oncology & carcinogenesis Drug resistance mtDNA haplogroups General Agricultural and Biological Sciences Pharmacogenomics ARPE-19 medicine.drug Human mitochondrial DNA haplogroup |
| Zdroj: | PeerJ PeerJ, Vol 8, p e9908 (2020) |
| ISSN: | 2167-8359 |
| Popis: | BackgroundDrug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual’s mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual’s mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations.MethodsThe present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels forALK,BRCA1,EGFR, andERBB2/HER2.ResultsResults indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%,p p = 0.0001) and [A+B] cybrids (24.67%,p = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B],p = 0.0270). (4) The expression levels decreased forALKin L (p p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased forEGFRin [A+B] cybrids (p = 0.0246) compared to untreated cybrids.ConclusionOur findings suggest that an individual’s mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment. |
| Databáze: | OpenAIRE |
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