Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism

Zhu, Zhenzhu; Wang, Zenghui; Zhang, Changli; Wang, Yanjun; Zhang, Hongmei; Gan, Zhenji; Guo, Zijian; Wang, Xiaoyong

doi:10.1039/c8sc04871a

Cited by 126 publications

(86 citation statements)

References 50 publications

(61 reference statements)

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“…This represents a major paradigm shift in cancer therapy and an urgently needed therapeutic intervention. Notably [1], design and expression of ATRAM-conjugated multifunctional GRA8 peptide to target tumor cells in vitro and in vivo [2], rATRAM-GRA8-M/AS induced HCT116 cell death by mitochondrial activation [3], rATRAM-GRA8-M/AS showed antitumor activity in HCT116 xenografts. We found that the ATRAMconjugated multifunctional GRA8 peptide might be exploit in therapeutic interventions against tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer is the primary cause of mortality worldwide, and in the United States cancer related deaths are second only to heart disease related mortality [1]. Metabolism is important not only in cancer development but also in its prevention [2,3]. Cancer cells have high rates of metabolism and require adenosine triphosphate (ATP) for their survival, proliferation and growth.…”

Section: Introductionmentioning

confidence: 99%

“…Therapeutic approaches that target mitochondria are considered to provide novel means to combat cancer and to reduce associated mortality and even to reverse the oncogenic process. Such metabolic intervening measures, called "metabolic resuscitation", employ either nutritional or pharmacological agents to improve mitochondrial function [2,4,7,8]. However, the underlying mechanisms for the metabolic resuscitation induced by the dense granule protein GRA8 of Toxoplasma gondii (T. gondii) in tumor cells are yet to be investigated [8].…”

Section: Introductionmentioning

confidence: 99%

“…SIRT3 can act like a tumor suppressor as well as an oncogene, and thus modulate cell death by affecting the main regulatory factors and their signaling pathways in cancer [5,6,14,15]. Thus, the GRA8-mediated cellular mechanisms that regulate mitochondrial metabolism could be exploited in therapeutic approaches against tumors similar to strategies that have been used against sepsis [2,8,16].…”

Section: Introductionmentioning

confidence: 99%

“…We investigated the multifunctional GRA8 peptide for mitochondrial metabolic reprogramming and its conjugation with the acidity-triggered rational membrane (ATRAM) to provide a better and effective strategy for delivering the anti-cancer therapeutics. Notably [1], Design and expression of ATRAM-conjugated multifunctional GRA8 peptide to target tumor cells in vitro and in vivo [2], rATRAM-GRA8-M/AS induced HCT116 cell death by mitochondrial activation [3], rATRAM-GRA8-M/AS showed antitumor activity in HCT116 xenografts.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

et al. 2020

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Targeted tumor and efficient, specific biological drug delivery in vivo has been one of the main challenges in protein-based cancer-targeted therapies. Mitochondria are potential therapeutic targets for various anti-cancer drugs. We have previously reported that protein kinase Cα-mediated phosphorylation of Toxoplasma gondii GRA8 is required for mitochondrial trafficking and regulating the interaction of the C-terminal of GRA8 with ATP5A1/SIRT3 in mitochondria. Furthermore, SIRT3 facilitates ATP5A1 deacetylation, mitochondrial activation, and subsequent antiseptic activity in vivo. Herein we developed a recombinant acidity-triggered rational membrane (ATRAM)-conjugated multifunctional GRA8 peptide (rATRAM-G8-M/AS) comprising ATRAM as the cancer-targeting cell-penetrating peptide, and essential/ minimal residues for mitochondrial targeting or ATP5A1/SIRT3 binding. This peptide construct showed considerably improved potency about cancer cell death via mitochondria activity and biogenesis compared with rGRA8 alone in HCT116 human carcinoma cells, reaching an IC 50 value of up to 200-fold lower in vitro and 500-fold lower in vivo. Notably, rATRAM-G8-M/AS treatment showed significant therapeutic effects in a mouse xenograft model through mitochondrial metabolic resuscitation, and it produced negligible immunogenicity and immune responses in vivo. Thus, these results demonstrate that rATRAM-G8-M/AS represents a useful therapeutic strategy against tumors, particularly colon cancer. This strategy represents an urgently needed paradigm shift for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

et al. 2020

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Amorphous Ultra‐Small Fe‐Based Nanocluster Engineered and ICG Loaded Organo‐Mesoporous Silica for GSH Depletion and Photothermal‐Chemodynamic Synergistic Therapy

Tian

Zhu

et al. 2022

Adv Healthcare Materials

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Intracellular oxidative amplification can effectively destroy tumor cells. Additionally, Fe-mediated Fenton reaction often converts cytoplasm H 2 O 2 to generate extensive hypertoxic hydroxyl radical ( • OH), leading to irreversible mitochondrion damage for tumor celleradication, which is widely famous as tumor chemodynamic therapy (CDT). Unfortunately, intracellular overexpressed glutathione (GSH) always efficiently scavenges • OH, resulting in the significantly reduced CDT effect. To overcome this shortcoming and improve the oxidative stress in cytoplasm, Fe 3 O 4 ultrasmall nanoparticle encapsulated and ICG loaded organo-mesoporous silica nanovehicles (omSN@Fe-ICG) are constructed to perform both photothermal and GSH depletion to enhance the Fenton-like CDT, by realizing intracellular oxidative stress amplification. After this nanoagents are internalized, the tetrasulfide bonds in the dendritic mesoporous framework can be decomposed with GSH to amplify the toxic ROS neration by selectively converting H 2 O 2 to hydroxyl radicals through the released Fe-based nanogranules. Furthermore, the NIR laser-induced hyperthermia can further improve the Fenton reaction rate that simultaneously destroyed the mitochondria. As a result, the GSH depletion and photothermal assisted CDT can remarkably improve the tumor eradication efficacy.

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Nanocatalytic Innate Immunity Activation by Mitochondrial DNA Oxidative Damage for Tumor‐Specific Therapy

et al. 2021

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The innate immune system plays a key role in protecting the human body from tumors, which, unfortunately, is largely counteracted by their immune‐suppression function. Such an immune suppression has been reported to be induced by the immunosuppressive microenvironment, including the exhausted cytotoxic T lymphocytes (CTLs) and tumor‐promoting M2‐polarized macrophages. Here, a novel tumor‐immunotherapeutic modality based on the nanocatalytic innate immunity activation by tumor‐specific mitochondrial DNA (mtDNA) oxidative damage is proposed. In detail, a nanocatalytic medicine, Fe2+–Ru2+‐loaded mesoporous silica nanoparticle named as MSN‐Ru2+/Fe2+ (MRF), is constructed to induce oxidative damage in the mtDNA of tumor cells. Such an oxidative mtDNA is able to escape from the tumor cells and acts as an immunogenic damage‐associated molecular pattern to M1‐polarize tumor‐associated macrophages (TAMs), resulting in the reactivated immunoresponse of macrophages against cancer cells, and the subsequent inflammatory response of innate immunity. Most importantly, the treatment strategy based on regulating the innate immune response of TAMs not only stops the primary tumor progression, but also almost completely inhibits the growth of distant tumors in the periods of treatments.

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Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism

Abstract: Monofunctional platinum complexes restrain lung cancer through disrupting mitochondrial oxidative phosphorylation and glycolysis in addition to damaging nuclear and mitochondrial DNA.

Cited by 126 publications

References 50 publications

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

Amorphous Ultra‐Small Fe‐Based Nanocluster Engineered and ICG Loaded Organo‐Mesoporous Silica for GSH Depletion and Photothermal‐Chemodynamic Synergistic Therapy

Nanocatalytic Innate Immunity Activation by Mitochondrial DNA Oxidative Damage for Tumor‐Specific Therapy

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