High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells

Abstract Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable diffe...

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Autores principales:	Jiaxin Sun, Chirag B. Patel, Taichang Jang, Milton Merchant, Chen Chen, Shiva Kazerounian, Anne R. Diers, Michael A. Kiebish, Vivek K. Vishnudas, Stephane Gesta, Rangaprasad Sarangarajan, Niven R. Narain, Seema Nagpal, Lawrence Recht
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f351ed5583a042e9aacf892af8e97331
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spelling	oai:doaj.org-article:f351ed5583a042e9aacf892af8e973312021-12-02T16:45:53ZHigh levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells10.1038/s41598-020-70969-02045-2322https://doaj.org/article/f351ed5583a042e9aacf892af8e973312020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70969-0https://doaj.org/toc/2045-2322Abstract Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable difference. Co-enzyme Q10 (CoQ10) an endogenous mitochondrial resident molecule, plays an important role in mitochondrial redox homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ10) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.Jiaxin SunChirag B. PatelTaichang JangMilton MerchantChen ChenShiva KazerounianAnne R. DiersMichael A. KiebishVivek K. VishnudasStephane GestaRangaprasad SarangarajanNiven R. NarainSeema NagpalLawrence RechtNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jiaxin Sun Chirag B. Patel Taichang Jang Milton Merchant Chen Chen Shiva Kazerounian Anne R. Diers Michael A. Kiebish Vivek K. Vishnudas Stephane Gesta Rangaprasad Sarangarajan Niven R. Narain Seema Nagpal Lawrence Recht High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
description	Abstract Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable difference. Co-enzyme Q10 (CoQ10) an endogenous mitochondrial resident molecule, plays an important role in mitochondrial redox homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ10) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.
format	article
author	Jiaxin Sun Chirag B. Patel Taichang Jang Milton Merchant Chen Chen Shiva Kazerounian Anne R. Diers Michael A. Kiebish Vivek K. Vishnudas Stephane Gesta Rangaprasad Sarangarajan Niven R. Narain Seema Nagpal Lawrence Recht
author_facet	Jiaxin Sun Chirag B. Patel Taichang Jang Milton Merchant Chen Chen Shiva Kazerounian Anne R. Diers Michael A. Kiebish Vivek K. Vishnudas Stephane Gesta Rangaprasad Sarangarajan Niven R. Narain Seema Nagpal Lawrence Recht
author_sort	Jiaxin Sun
title	High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
title_short	High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
title_full	High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
title_fullStr	High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
title_full_unstemmed	High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
title_sort	high levels of ubidecarenone (oxidized coq10) delivered using a drug-lipid conjugate nanodispersion (bpm31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/f351ed5583a042e9aacf892af8e97331
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High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells

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