Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups

PeerJ

article

Sina Abedi¹  Gregory Yung¹  Shari R. Atilano¹  Kunal Thaker¹  Steven Chang¹  Marilyn Chwa¹  Kevin Schneider¹  Nitin Udar¹  Daniela Bota²  M. Cristina Kenney¹ 

[1] Gavin Herbert Eye Institute, University of California;Department of Neurology, Neuro-Oncology Division, University of California;Department of Pathology and Laboratory Medicine, University of California

关键词: Cisplatin;    Mitochondria;    Cybrids;    Drug resistance;    mtDNA haplogroups;    ARPE-19;    Pharmacogenomics;    Anticancer;   

DOI  :  10.7717/peerj.9908

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

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 for ALK, BRCA1, EGFR, and ERBB2/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 < 0.012) < D (24.86%, p = 0.0001) and [A+B] cybrids (24.67%, p[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.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.

【 授权许可】

CC BY