A Cytochrome <i>c</i>‐Chlorotoxin Hybrid Protein as a Possible Antiglioma Drug

Delinois, Louis J.; Peón, Harold; Villalobos‐Santos, Juan C.; Ramírez‐Paz, Josell; Miller, Jennifer K.; Griebenow, Kai; Tinoco, Arthur D.

doi:10.1002/cmdc.202000373

Cited by 6 publications

(5 citation statements)

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“…This attribute was apparent in cytotoxicity experiments with Cyt c , a protein that induces apoptosis by activating a caspase-dependent proteolytic cascade in the cytosol (Figures S52 and S53). ,− We compared the activity of Cyt c – 1 –cR 10 in live cells with that of Cyt c conjugated with cR 10 via irreversible Lys amidation (Cyt c –BCN–cR 10 ) (Figure S54). Specifically, we assessed the toxicity of each conjugate to M21 cells using an MTS assay for metabolic activity.…”

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confidence: 99%

Modular Diazo Compound for the Bioreversible Late-Stage Modification of Proteins

et al. 2023

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We introduce a versatile strategy for the bioreversible modification of proteins. Our strategy is based on a tricomponent molecule, synthesized in three steps, that incorporates a diazo moiety for chemoselective esterification of carboxyl groups, a pyridyl disulfide group for late-stage functionalization with thiolated ligands, and a self-immolative carbonate group for esterase-mediated cleavage. Using cytochrome c (Cyt c) and the green fluorescent protein (GFP) as models, we generated protein conjugates modified with diverse domains for cellular delivery that include a small molecule, targeting and cell-penetrating peptides (CPPs), and a large polysaccharide. As a proof of concept, we used our strategy to effect the delivery of proteins into the cytosol of live mammalian cells in the presence of serum. The cellular delivery of functional Cyt c, which induces apoptosis, highlighted the advantage of bioreversible conjugation on a carboxyl group versus irreversible conjugation on an amino group. The ease and utility of this traceless modification provide new opportunities for chemical biologists.

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confidence: 99%

Modular Diazo Compound for the Bioreversible Late-Stage Modification of Proteins

et al. 2023

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“…Tumor-targeting peptides can be used as a tumor-targeting domain of CARs as an alternative to designs based on antibodies. Chlorotoxin (CLTX) is a small, nature-derived peptide able to bind to primary brain tumors while exhibiting negligible affinity for normal tissues [ 124 ]. On incorporation into CARs, CLTX reroutes T cells towards targeted tumor detection with little detectable off-target consequences.…”

Section: Clinical Considerationsmentioning

confidence: 99%

CAR T cells: engineered immune cells to treat brain cancers and beyond

et al. 2023

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Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy and/or chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential targets for immunotherapy-based targeting, including but not limited to EGFRvIII, IL13Rα2, and HER2. The outstanding clinical responses to CAR T cell-based treatments in patients with hematological malignancies have generated interest in using this approach to treat solid tumors. Research results to date support the astounding clinical response rates of CD19-targeted CAR T cells, early clinical experiences in brain tumors demonstrating safety and evidence for disease-modifying activity, and the promise for further advances to ultimately assist patients clinically. However, several variable factors seem to slow down the progress rate regarding treating brain cancers utilizing CAR T cells. The current study offers a thorough analysis of CAR T cells’ promise in treating brain cancer, including design and delivery considerations, current strides in clinical and preclinical research, issues encountered, and potential solutions.

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“…In another system, cyt c was fused to transferrin, for targeting cancer types in which the transferrin receptor is overexpressed, including lung cancer [ 48 ]. For targeting glioma cells, cyt c was fused to the neurotoxin peptide chlorotoxin, to promote uptake into brain cells [ 49 ]. In another fusion system, cyt c was conjugated with galactosylated albumin, which is recognized by receptors on hepatocellular carcinoma cells [ 50 ].…”

Section: Systems For Therapeutic Delivery Of Cyt C ...mentioning

confidence: 99%

Cytochrome c in cancer therapy and prognosis

Pessoa

2022

Bioscience Reports

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Cytochrome c (cyt c) is an electron transporter of the mitochondrial respiratory chain. Upon permeabilization of the mitochondrial outer membrane, cyt c is released into the cytoplasm, where it triggers the intrinsic pathway of apoptosis. Cytoplasmic cyt c can further reach the bloodstream. Apoptosis inhibition is one of the hallmarks of cancer and its induction in tumors is a widely used therapeutic approach. Apoptosis inhibition and induction correlate with decreased and increased serum levels of cyt c, respectively. The quantification of cyt c in the serum is useful in the monitoring of patient response to chemotherapy, with potential prognosis value. Several highly sensitive biosensors have been developed for the quantification of cyt c levels in human serum. Moreover, the delivery of exogenous cyt c to the cytoplasm of cancer cells is an effective approach for inducing their apoptosis. Similarly, several protein-based and nanoparticle-based systems have been developed for the therapeutic delivery of cyt c to cancer cells. As such, cyt c is a human protein with promising value in cancer prognosis and therapy. In addition, its thermal stability can be extended through PEGylation and ionic liquid storage. These processes could contribute to enhancing its therapeutic exploitation in clinical facilities with limited refrigeration conditions. Here, I discuss these research lines and how their timely conjunction can advance cancer therapy and prognosis.

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A Cytochrome c‐Chlorotoxin Hybrid Protein as a Possible Antiglioma Drug

Cited by 6 publications

References 47 publications

Modular Diazo Compound for the Bioreversible Late-Stage Modification of Proteins

Modular Diazo Compound for the Bioreversible Late-Stage Modification of Proteins

CAR T cells: engineered immune cells to treat brain cancers and beyond

Cytochrome c in cancer therapy and prognosis

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