Using Human 'Personalized' Cybrids to Identify Drugs/Agents That Can Regulate Chronic Lymphoblastic Leukemia Mitochondrial Dysfunction

• Published in: International journal of molecular sciences Vol. 24; no. 13; p. 11025
• Main Authors: Singh, Lata, Atilano, Shari, Chwa, Marilyn, Singh, Mithalesh K, Ozgul, Mustafa, Nesburn, Anthony, Kenney, M Cristina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2023; MDPI
• Subjects: Acute myeloid leukemia; Antioxidants; Antioxidants - metabolism; Apoptosis; Bendamustine; Cancer; Cancer therapies; Chemotherapy; chronic lymphoblastic leukemia; Chronic lymphocytic leukemia; Customization; cybrid; Cybrids; Disease; Drugs; Functional foods; Functional foods & nutraceuticals; Gene expression; Genes; Humans; Hypotheses; ibrutinib; Inflammation; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Myeloid, Acute - metabolism; Lipoic acid; Lymphocytic leukemia; Melatonin; Membrane potential; Metabolism; Metabolites; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; NOX4 protein; nutraceutical; Oncology, Experimental; Physiological aspects; Polymerase chain reaction; Reactive Oxygen Species - metabolism; Resveratrol; Scientific equipment and supplies industry; Survivability; United States; California; ibrutinib; chronic lymphoblastic leukemia; cybrid; mitochondria; nutraceutical
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241311025

This study uses personalized chronic lymphoblastic leukemia (CLL) cybrid cells to test various drugs/agents designed to improve mitochondrial function and cell longevity. Age-matched control (NL) and CLL cybrids were created. The NL and CLL cybrids were treated with ibrutinib (Ibr-10 μM), mitochondrial-targeted nutraceuticals such as alpha lipoic acid (ALA-1 mM), amla (Aml-300 μg), melatonin (Mel-1 mM), resveratrol (Res-100 μM) alone, or a combination of ibrutinib with nutraceuticals (Ibr + ALA, Ibr + Aml, Ibr + Mel, or Ibr + Res) for 48 h. MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide), H2DCFDA(2',7' Dichlorodihydrofluorescein diacetate), and JC1 assays were used to measure the cellular metabolism, intracellular ROS levels, and mitochondrial membrane potential (∆ψm), respectively. The expression levels of genes associated with antioxidant enzymes ( , , and ), apoptosis ( and ), and inflammation ( , , , and ) were measured using quantitative real-time PCR (qRT-PCR). CLL cybrids treated with Ibr + ALA, Ibr + Aml, Ibr + Mel, and Ibr + Res had (a) reduced cell survivability, (b) increased ROS production, (c) increased ∆ψm levels, (d) decreased antioxidant gene expression levels, and (e) increased apoptotic and inflammatory genes in CLL cybrids when compared with ibrutinib-alone-treated CLL cybrids. Our findings show that the addition of nutraceuticals makes the CLL cybrids more pro-apoptotic with decreased cell survival compared with CLL cybrids exposed to ibrutinib alone.