Mitochondrial Relocation of a Common Synthetic Antibiotic: A Non-genotoxic Approach to Cancer Therapy

Sunwoo, Kyoung; Won, Miae; Ko, Kwanyoung; Choi, Miri; Arambula, Jonathan F.; Gil, Sung; Sessler, Jonathan L.; Verwilst, Peter; Kim, Jong Seung

doi:10.1016/j.chempr.2020.03.004

Cited by 39 publications

(38 citation statements)

References 28 publications

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“…Bulleted In our previous work, the low toxicity of CFX derivatives was verified within various cell lines, including human fibroblast cell line (BJ) and non-tumorigenic epithelial cell line (MCF 10A) [22]. We additionally performed the hemolysis assay against mouse red blood cells (RBCs) to confirm the effect of the CFX and CFX derivatives toward the hemolysis of MSSA ( Figure S3).…”

Section: Cytotoxicity Assaymentioning

confidence: 94%

“…The TPP moiety was conjugated on the carboxylic acid moiety of CFX via esterification (for CFX-ester-PPh3) and amide coupling (for CFX-amide-PPh3) using triphenyl-phosphonium propyl alcohol, and triphenylphosphonium propyl amine, respectively. The derivatives were prepared using the protocol developed by our group (previous work: drug repositioning of antibiotic for anticancer) (Scheme S1 and S2 in Supplementary material) [22]. CFX-ester-PPh3 was prepared by using t-butyloxycarbonyl (Boc)-protected CFX and triphenyl-phosphonium propyl alcohol, with potassium carbonate (K2CO3) in N,N-dimethylformamide (DMF).…”

Section: Rationalmentioning

confidence: 99%

“…These results suggest that the CFX-PPh3 derivatives could affect the delay in the acquisition of resistance than CFX. TPP-conjugated CFX derivatives were prepared using previously published protocols (details in Supporting information) [22].…”

Section: Gene Expression Analysismentioning

confidence: 99%

“…TPP-conjugated CFX derivatives were prepared using previously published protocols (details in Supporting information) [22].…”

Section: Preparation Of Cfx-pph3 Derivativesmentioning

confidence: 99%

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Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

Kang¹,

Sunwoo²,

Jung³

et al. 2020

Preprint

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Multidrug resistant (MDR) bacteria have become a severe problem for public health. Developing new antibiotics for MDR bacteria is difficult, from inception to the clinically approved stage. Here, we have used a new approach; we have modified the antibiotic, ciprofloxacin (CFX), with triphenylphosphonium (TPP, PPh3) moiety via ester- (CFX-ester-PPh3) and amide-coupling (CFX-ester-PPh3), to target bacterial membranes. In this study, we have evaluated the antibacterial activities of CFX and its derivatives against 16 species of bacteria, including MDR bacteria, using minimum inhibitory concentration (MIC) assay, morphological monitoring, and expression of resistance-related genes. TPP-conjugated CFX, CFX-ester-PPh3 and CFX-amide-PPh3 showed significantly improved antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, including MDR S. aureus (MRSA) strains. The MRSA ST5 5016 strain showed high antibacterial activity, with an MIC values of 11.12 µg/mL for CFX-ester-PPh3 and 2.78 µg/mL for CFX-amide-PPh3. The CFX derivatives inhibited biofilm formation in MRSA by more than 74.9% of CFX-amide-PPh3. In the sub-MIC, CFX derivates induced significant morphological changes in MRSA, including irregular deformation and membrane disruption, accompanied by a decrease in the level of resistance-related gene expression. With these promising results, this method is very likely to combat MDR bacteria, through a simple TPP moiety modification of known antibiotics, which can be readily prepared at clinical sites.

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Section: Cytotoxicity Assaymentioning

confidence: 94%

Section: Rationalmentioning

confidence: 99%

Section: Gene Expression Analysismentioning

confidence: 99%

“…TPP-conjugated CFX derivatives were prepared using previously published protocols (details in Supporting information) [22].…”

Section: Preparation Of Cfx-pph3 Derivativesmentioning

confidence: 99%

See 2 more Smart Citations

Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

Kang¹,

Sunwoo²,

Jung³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Mitochondria is a critical organelle for aerobic respiration and acts as the power source of cells [10] . Mitochondrial dysfunction is closely associated with multiple aspects of tumour occurrence and development [11–17] . Targeting mitochondria for pharmaceutical drugs can efficiently trigger mitochondrial dysfunction to improve the therapeutic efficiency [11–17] .…”

Section: Introductionmentioning

confidence: 99%

Regulating Twisted Skeleton to Construct Organ‐Specific Perylene for Intensive Cancer Chemotherapy

Wang

Chen

et al. 2021

Angewandte Chemie

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The systemic use of pharmaceutical drugs for cancer patients is a compromise between desirable therapy and side effects because of the intrinsic shortage of organ‐specific pharmaceutical drug. Design and construction of pharmaceutical drug to achieve the organ‐specific delivery is thus desperately desirable. We herein regulate perylene skeleton to effect organ‐specificity and present an example of lung‐specific distribution on the basis of bay‐twisted PDIC‐NC. We further demonstrate that PDIC‐NC can target into mitochondria to act as cellular respiration inhibitor, inducing insufficient production of adenosine triphosphate, promoting endogenous H2O2 and .OH burst, elevating calcium overload, efficiently triggering the synergistic apoptosis, autophagy and endoplasmic reticulum stress of lung cancer cells. The antitumor performance of PDIC‐NC is verified on in vivo xenografted, metastasis and orthotopic lung cancer, presenting overwhelming evidences for potentially clinical application. This study contributes a proof‐of‐concept demonstration of twisted perylene to well attain lung‐specific distribution, and meanwhile achieves intensive lung cancer chemotherapy.

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Spatio‐Temporally Reporting Dose‐Dependent Chemotherapy via Uniting Dual‐Modal MRI/NIR Imaging

Yan

Guo

et al. 2020

Angewandte Chemie

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Unpredictable in vivo therapeutic feedback of hydroxyl radical (.OH) efficiency is the major bottleneck of chemodynamic therapy. Herein, we describe novel Fenton‐based nanotheranostics NQ‐Cy@Fe&GOD for spatio‐temporally reporting intratumor .OH‐mediated treatment, which innovatively unites dual‐channel near‐infrared (NIR) fluorescence and magnetic resonance imaging (MRI) signals. Specifically, MRI signal traces the dose distribution of Fenton‐based iron oxide nanoparticles (IONPs) with high‐spatial resolution, meanwhile timely fluorescence signal quantifies .OH‐mediated therapeutic response with high spatio‐temporal resolution. NQ‐Cy@Fe&GOD can successfully monitor the intracellular release of IONPs and .OH‐induced NQO1 enzyme in living cells and tumor‐bearing mice, which makes a breakthrough in conquering the inherent unpredictable obstacles on spatio‐temporally reporting chemodynamic therapy, so as to manipulate dose‐dependent therapeutic process.

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Mitochondrial Relocation of a Common Synthetic Antibiotic: A Non-genotoxic Approach to Cancer Therapy

Cited by 39 publications

References 28 publications

Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

Regulating Twisted Skeleton to Construct Organ‐Specific Perylene for Intensive Cancer Chemotherapy

Spatio‐Temporally Reporting Dose‐Dependent Chemotherapy via Uniting Dual‐Modal MRI/NIR Imaging

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