Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

Jean, Sae Rin; Tulumello, David V.; Riganti, Chiara; Liyanage, Sanduni U.; Schimmer, Aaron D.; Kelley, Shana O.

doi:10.1021/acschembio.5b00268

Cited by 65 publications

(52 citation statements)

References 40 publications

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“…Recently, Jean et al 64 showed that mice treated with a chemically modified doxorubicin derivative, which exclusively enters mitochondria but not the nucleus, lack cardiotoxicity, arguing against a dominant contribution of mtDNA damage in the development of cardiomyopathy following anthracycline treatment. The authors suggest that altered nuclear expression of genes encoding mitochondrial biogenesis factors such as NRF1 and TFAM, is more relevant for the onset of cardiotoxicity than direct mitochondrial damage.…”

Section: Mechanisms Of Anthracycline-induced Cardiotoxicitymentioning

confidence: 99%

Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers

Henninger

Fritz

2017

Cell Death Dis

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Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures. Statins are anti-inflammatory and anti-oxidative drugs that are clinically well established for the prevention of cardiovascular diseases. They exhibit pleiotropic beneficial properties beyond cholesterol-lowering effects that most likely rest on the indirect inhibition of small Ras homologous (Rho) GTPases. The Rho GTPase Rac1 has been shown to be a major factor in the regulation of the pro-oxidative NADPH oxidase as well as in the regulation of type II topoisomerase. Both are discussed to play an important role in the pathophysiology of anthracycline-induced CHF. Therefore, off-label use of statins or novel Rac1 inhibitors might represent a promising pharmacological approach to gain control over chronic cardiotoxicity by interfering with key mechanisms of anthracycline-induced cardiomyocyte cell death.

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Section: Mechanisms Of Anthracycline-induced Cardiotoxicitymentioning

confidence: 99%

Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers

Henninger

Fritz

2017

Cell Death Dis

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“…Another exciting advantage of mitochondrial targeting for anticancer therapy is the amelioration of off‐target toxicities. When doxorubicin (DOX) was chemically modified into a mitochondrial‐targeted DOX, its cardiotoxicity was decreased, while maintaining its anticancer activity . Additionally, DOX targeted delivery to mitochondria can effectively improve the therapeutic efficacy of DOX in human cancer cell sensitive and resistant cancer .…”

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confidence: 99%

Multistage Targeting Strategy Using Magnetic Composite Nanoparticles for Synergism of Photothermal Therapy and Chemotherapy

Wang

Wei

Zhang

et al. 2017

Small

100

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Mitochondrial-targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin-loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core-shell-SS-shell architecture are composed of a core of Fe O colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near-infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment.

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“…On the other hand, mitochondria-targeting DOX (mtDOX) provided a means to limit drug efflux and inhibited mitochondrial DNA topoisomerase even in the efflux pump overexpressed cells. The same group reported that mtDOX eliminates nuclear effects associated with cardiotoxicity leading to mitochondrial biogenesis [51]. Although DOX has a high level of activity against cancer cells, side effects, such as dose-limiting cardiotoxicity, are a bottleneck for clinical usage.…”

Section: Mitochondria-targeted Peptidesmentioning

confidence: 99%

“…(A) Chemical structure of mitochondria-penetrating peptides (MPPs) conjugated with anticancer drug cisplatin (mtPt), (B) cell cytotoxicity of mtPt in A2780 WT(wild type) and cisplatin-resistant A2780CP70 cell for an incubation time of 72 h showing similar cytotoxicity in both cell lines, (C) chemical structure of MPP conjugated with anticancer drug doxorubicin (mtDox), (D) cell cytotoxicity of mtDox in A2780ADR for a treatment period of 24 h showing higher cytotoxicity of mtDox compared with Dox. (Copyright permission received from reference[51] and[52]). …”

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confidence: 99%

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

Jeena

Kim

Jin

et al. 2019

Cancers

107

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The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.In healthy cells, mitochondria execute a controlled regulation of multiple functions to maintain the cellular growth-death cycle. However, in the case of tumor cells, to meet the higher metabolic demand of rapidly proliferating cells, dysregulation of mitochondrial metabolism occurs [14,15]. The difference between cancer cell mitochondria and normal cells includes several functional alterations, such as mutation of mtDNA that lead to OXPHOS (oxidative phosphorylation) inhibition and thus deficient respiration and ATP generation, mutation of mtDNA-encoded mitochondrial enzymes, such as SDH (succinate dehydrogenase), IDH1 (isocitrate dehydrogenase 1), IDH2 (isocitrate dehydrogenase 2) [16], and structural differences, such as higher membrane potential of cancer cell mitochondria and higher basicity inside the mitochondrial lumen. The evasion of cell death or inhibition of mitochondria-mediated apoptosis is a hallmark for cancer. Mitochondria generate ROS, which is necessary for signaling under normal conditions. However, when apoptosis is inhibited in the case of cancer, ROS contributes to the neoplastic transformation. Furthermore, for supporting tumor cell survival under harsh tumorigenic conditions, such as nutrient depletion and hypoxia, mitochondria provide flexibility in several pathways either by up-or downregulation [17]. This altered mitochondrial metabolism of cancer cells compared with that of their normal counterparts is advantageous for the selective targeting of cancer mitochondria in therapeutics, which focuses on the cancer mitochondria specific features [18]. Directing the therapeutic agent to the mitochondria is an efficient way of eliminating cancer cells because the designed drug molecules could act at the central point of the cell, and therefore, engineering mitochondrial-targeted therapeutic agents have gained much interest in cancer thera...

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Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

Cited by 65 publications

References 40 publications

Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers

Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers

Multistage Targeting Strategy Using Magnetic Composite Nanoparticles for Synergism of Photothermal Therapy and Chemotherapy

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

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