Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups
Background Drug 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 variatio...
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doaj-ef7b066f4c99462ba14fb3f9dd0f107a2020-11-25T02:06:06ZengPeerJ Inc.PeerJ2167-83592020-10-018e990810.7717/peerj.9908Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroupsSina Abedi0Gregory Yung1Shari R. Atilano2Kunal Thaker3Steven Chang4Marilyn Chwa5Kevin Schneider6Nitin Udar7Daniela Bota8M. Cristina Kenney9Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaDepartment of Neurology, Neuro-Oncology Division, University of California, Irvine, CA, United States of AmericaGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of AmericaBackground Drug 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. Methods The 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 for ALK, BRCA1, EGFR, and ERBB2/HER2. Results Results 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 < 0.012) < D (24.86%, 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 for ALK in L (p < 0.0001) and [A+B] (p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased for EGFR in [A+B] cybrids (p = 0.0246) compared to untreated cybrids. Conclusion Our 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.https://peerj.com/articles/9908.pdfCisplatin Mitochondria Cybrids Drug resistance mtDNA haplogroupsARPE-19 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sina Abedi Gregory Yung Shari R. Atilano Kunal Thaker Steven Chang Marilyn Chwa Kevin Schneider Nitin Udar Daniela Bota M. Cristina Kenney |
spellingShingle |
Sina Abedi Gregory Yung Shari R. Atilano Kunal Thaker Steven Chang Marilyn Chwa Kevin Schneider Nitin Udar Daniela Bota M. Cristina Kenney Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups PeerJ Cisplatin Mitochondria Cybrids Drug resistance mtDNA haplogroups ARPE-19 |
author_facet |
Sina Abedi Gregory Yung Shari R. Atilano Kunal Thaker Steven Chang Marilyn Chwa Kevin Schneider Nitin Udar Daniela Bota M. Cristina Kenney |
author_sort |
Sina Abedi |
title |
Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups |
title_short |
Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups |
title_full |
Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups |
title_fullStr |
Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups |
title_full_unstemmed |
Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups |
title_sort |
differential effects of cisplatin on cybrid cells with varying mitochondrial dna haplogroups |
publisher |
PeerJ Inc. |
series |
PeerJ |
issn |
2167-8359 |
publishDate |
2020-10-01 |
description |
Background Drug 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. Methods The 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 for ALK, BRCA1, EGFR, and ERBB2/HER2. Results Results 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 < 0.012) < D (24.86%, 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 for ALK in L (p < 0.0001) and [A+B] (p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased for EGFR in [A+B] cybrids (p = 0.0246) compared to untreated cybrids. Conclusion Our 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. |
topic |
Cisplatin Mitochondria Cybrids Drug resistance mtDNA haplogroups ARPE-19 |
url |
https://peerj.com/articles/9908.pdf |
work_keys_str_mv |
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