An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a bro... more An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance.
Proceedings of the National Academy of Sciences, 2022
Significance Here we address the important question of cross-talk between the mitochondria and cy... more Significance Here we address the important question of cross-talk between the mitochondria and cytosol. We show that the inner mitochondrial protein, MiNT, interacts with a protein on the outer mitochondrial membrane (mNT). This interaction occurs within the major outer membrane protein VDAC1. Inside the inner space of VDAC1, MiNT transfers its [2Fe-2S] clusters to mNT, which was shown to be a [2Fe-2S] cluster donor protein that donates its cluster(s) to apo-acceptor proteins residing in the cytosol. Hence, we suggest a pathway for transferring [2Fe-2S] clusters from inside the mitochondria to the cytosol.
UiO-66 metal–organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahed... more UiO-66 metal–organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahedra provide superior biomarker-responsive hybrid nano-carriers for biomedical applications.
The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and ... more The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and neurodegenerative diseases. It was found to control different calcium, reactive oxygen species (ROS), and iron signaling mechanisms. However, since most studies of CISD2 to date were conducted with cells that constitutively lack, overexpress, or contain mutations in CISD2, the relationships between these different signaling processes are unclear. To address the hierarchy of signaling events occurring in cells upon CISD2 disruption, we developed an inducible system to express CISD2, or the dominant-negative H114C inhibitor of CISD2, in human breast cancer cells. Here, we report that inducible disruption of CISD2 function causes an immediate disruption in mitochondrial labile iron (mLI), and that this disruption results in enhanced mitochondrial ROS (mROS) levels. We further show that alterations in cytosolic and ER calcium levels occur only after the changes in mLI and mROS levels happen and are unrelated to them. Interestingly, disrupting CISD2 function resulted in the enhanced expression of the tumor suppressor thioredoxin-interacting protein (TXNIP) that was dependent on the accumulation of mLI and associated with ferroptosis activation. CISD2 could therefore regulate the expression of TXNIP in cancer cells, and this regulation is dependent on alterations in mLI levels.
The reversible and switchable triggered reconfiguration of tetrahedra nanostructures from monomer... more The reversible and switchable triggered reconfiguration of tetrahedra nanostructures from monomer tetrahedra structures into dimer or trimer structures is introduced. The triggered bridging of monomer tetrahedra by K+‐ion‐stabilized G‐quadruplexes or T‐A•T triplexes leads to dimer or trimer tetrahedra structures that are separated by crown ether or basic pH conditions, respectively. The signal‐triggered dimerization/trimerization of DNA tetrahedra structures is used to develop multiplexed miRNA‐sensing platforms, and the tetrahedra mixture is used for intracellular sensing and imaging of miRNAs.
The sensing modules for analyzing miRNAs or the endonucleases consist of tetrahedra functionalize... more The sensing modules for analyzing miRNAs or the endonucleases consist of tetrahedra functionalized with three different fluorophore-quencher pairs in spatially quenched configurations, and hairpin units acting as recognition elements for the analytes. Three different miRNAs (miRNA-21; miRNA-221 and miRNA-155) or three different endonucleases (Nt.BbvCI; EcoRI and HindIII) uncage the respective hairpins, leading to the switched-on fluorescence of the respective fluorophores and to the multiplex detection of the respective analytes. In addition, a tetrahedron module for the multiplexed analysis of aptamer ligand complexes (ligands = ATP, thrombin, VEGF) is introduced. The module includes edges modified with three spatially separated fluorophore-quencher pairs that were stretched by the respective aptamer strands to yield a switched-on fluorescent state. Formation of the respective aptamer ligands reconfigures the edges into fluorophore-quenched caged-hairpin structures that enable the multiplexed analysis of the aptamer-ligand complexes. The facile permeation of the tetrahedra structures into cells is used for the imaging of MCF-7 and HepG2 cancer cells, and their discrimination from normal epithelial MCF-10A breast cells.
Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic d... more Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito‐C. Mito‐C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito‐C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF‐1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER–mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito‐C counteracts dengue virus‐induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including M...
A method to assemble stimuli-responsive nucleic acid-based hydrogel-stabilized microcapsule-in-mi... more A method to assemble stimuli-responsive nucleic acid-based hydrogel-stabilized microcapsule-in-microcapsule systems is introduced. An inner aqueous compartment stabilized by stimuli-responsive hydrogel-layer (ca. 150 nm) provides the inner microcapsule (diameter ca. 2.5 µm). The inner microcapsule is separated from the outer aqueous compartment stabilized by an outer stimuli-responsive hydrogel layer (thickness of ca. 150 nm) that yields a microcapsule-in-microcapsule system. Different loads, e.g. tetramethyl rhodamine-dextran (TMR-D) and CdSe/ZnS quantum dots (QDs), are loaded in the inner and outer aqueous compartments. The hydrogel layers exist in a higher stiffness state that prevents inter-reservoir or leakage of the loads from the respective aqueous compartments. Subjecting the inner hydrogel layer to Zn 2+ -ion and/or the outer hydrogel layer to acidic pH or crown ether leads to the triggered separation of the bridging units associated with the respective hydrogel layers. This results in hydrogel layers of lower stiffness allowing either the mixing of the loads occupying the two aqueous compartments, the guided release of the load from the outer aqueous compartment, or the release of the loads from the two aqueous compartments. In addition, the pH-responsive microcapsule-in-microcapsule system is loaded with glucose oxidase (GOx) in the inner aqueous compartment and insulin in the outer aqueous compartment. Glucose permeates across the two hydrogel layers resulting in the glucose oxidase catalyzed aerobic oxidation of glucose to gluconic acid. The acidification of the microcapsule-in-microcapsule system leads to the triggered unlocking of the outer, pH-responsive hydrogel layer and to the release of insulin. The pH-stimulated release of insulin is controlled by the concentration of glucose. While at normal glucose levels, the release of insulin is practically prohibited, the dose-controlled release of insulin in the entire concentration range of diabetic concern is demonstrated. Also, switchable ON/OFF release of insulin is achieved highlighting an autonomous glucose-responsive microdevice operating as an "artificial pancreas" for the release of insulin.
Nucleic acid-modified UiO-68 metal-organic framework nanoparticles, NMOFs, are loaded with the an... more Nucleic acid-modified UiO-68 metal-organic framework nanoparticles, NMOFs, are loaded with the anticancer drug camptothecin (or drug models), and the loaded NMOFs are capped with sequence-specific duplex units. The NMOFs are unlocked by the biocatalytic decomposition of the duplex capping units that result in the release of the drug (or drug models). The enzymes used are DNase I, a nicking enzyme (Nt.BbvCI), an endonuclease (EcoRI), and an exonuclease III (Exo III). Camptothecin-loaded NMOFs, capped by tailored hairpin nucleic acids being cooperatively unlocked by adenosine triphosphate (ATP), that is overexpressed in cancer cells, and Exo III are prepared. The camptothecin-loaded NMOFs reveal that selective cytotoxicity toward MDA-MB-231 cancer cells and ≈55% apoptosis of the cancer cells is observed after 5 days of treatment with the NMOFs, while only ≈15% apoptosis of epithelial MCF-10A breast cells is observed.
Nanoparticles consisting of metal–organic frameworks (NMOFs) modified with nucleic acid binding s... more Nanoparticles consisting of metal–organic frameworks (NMOFs) modified with nucleic acid binding strands are synthesized. The NMOFs are loaded with a fluorescent agent or with the anticancer drug doxorubicin, and the loaded NMOFs are capped by hybridization with a complementary nucleic acid that includes the ATP‐aptamer or the ATP‐AS1411 hybrid aptamer in caged configurations. The NMOFs are unlocked in the presence of ATP via the formation of ATP‐aptamer complexes, resulting in the release of the loads. As ATP is overexpressed in cancer cells, and since the AS1411 aptamer recognizes the nucleolin receptor sites on the cancer cell membrane, the doxorubicin‐loaded NMOFs provide functional carriers for targeting and treatment of cancer cells. Preliminary cell experiments reveal impressive selective permeation of the NMOFs into MDA‐MB‐231 breast cancer cells as compared to MCF‐10A normal epithelial breast cells. High cytotoxic efficacy and targeted drug release are observed with the ATP‐...
We reveal a novel interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are ... more We reveal a novel interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are overexpressed in many types of cancer cells, and propose that this interaction is required for apoptosis activation in cancer cells. A peptide derived from the interaction interface inhibits apoptosis in cells.
Zeolitic Zn-imidazolate cross-linked framework nanoparticles, ZIF-8 NMOFs, are used as "smar... more Zeolitic Zn-imidazolate cross-linked framework nanoparticles, ZIF-8 NMOFs, are used as "smart" glucose-responsive carriers for the controlled release of drugs. The ZIF-8 NMOFs are loaded with the respective drug and glucose oxidase (GOx), and the GOx-mediated aerobic oxidation of glucose yields gluconic acid and HO. The acidification of the NMOFs' microenvironment leads to the degradation of the nanoparticles and the release of the loaded drugs. In one sense-and-treat system, GOx and insulin are loaded in the NMOFs. In the presence of glucose, the nanoparticles are unlocked, resulting in the release of insulin. The release of insulin is controlled by the concentration of glucose. In the second sense-and-treat system, the NMOFs are loaded with the antivascular endothelial growth factor aptamer (VEGF aptamer) and GOx. In the presence of glucose, the ZIF-8 NMOFs are degraded, leading to the release of the VEGF aptamer, which acts as a potential inhibitor of the angiogenet...
Cancer cells accumulate high levels of iron and reactive oxygen species (ROS) to promote their hi... more Cancer cells accumulate high levels of iron and reactive oxygen species (ROS) to promote their high metabolic activity and proliferation rate. However, high levels of iron and ROS can also lead to enhanced oxidative stress and the activation of cell death pathways such as apoptosis and ferroptosis. This has led to the proposal that different drugs that target iron and/or ROS metabolism could be used as anticancer drugs. However, due to the complex role iron and ROS play in cells, the majority of these drugs yielded mixed results, highlighting a critical need to identify new players in the regulation of iron and ROS homeostasis in cancer cells. Recent Advances: NEET proteins belong to a newly discovered class of iron-sulfur (2Fe-2S) proteins required for the regulation of iron and ROS homeostasis in cells. Recent studies revealed that the NEET proteins NAF-1 (CISD2) and mitoNEET (CISD1) play a critical role in promoting the proliferation of cancer cells, supporting tumor growth and m...
Proceedings of the National Academy of Sciences of the United States of America, Jan 9, 2018
The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important... more The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased ac...
Drug-loaded DNA-capped metal–organic framework nanoparticles are unlocked by pH or Mg2+ ions/ATP ... more Drug-loaded DNA-capped metal–organic framework nanoparticles are unlocked by pH or Mg2+ ions/ATP triggers, resulting in the release of the loads.
Journal of Chemical Information and Modeling, 2016
Specific iron chelation is a validated strategy in anticancer drug discovery. However, only a few... more Specific iron chelation is a validated strategy in anticancer drug discovery. However, only a few chemical classes (4-5 categories) have been reported to date. We discovered in silico 5 new structurally diverse iron chelators by screening through models based on previously known chelators. To encompass a larger chemical space and propose newer scaffolds, we used our Iterative Stochastic Elimination (ISE) algorithm for model building and subsequent virtual screening (VS). The ISE models were developed by training a dataset of 130 reported iron chelators. The developed models are statistically significant with area under the receiver operating curve greater than 0.9. The models were used to screen the Enamine chemical database of ~1.8 million molecules. The top ranked 650 molecules were reduced to 50 diverse structures, and a few others were eliminated due to the presence of reactive groups. Finally, 34 molecules were purchased and tested in vitro. Five compounds were identified with significant iron chelation activity in Cal-G assay. Intracellular iron-chelation study revealed one compound as equivalent in potency to the iron chelating "gold standards" DFO and DFP. The amount of discovered positives (5 out of 34) is expected by the realistic enrichment factor of the model.
Journal of the American Chemical Society, Jul 20, 2016
A method to assemble light-responsive or pH-responsive microcapsules loaded with different loads ... more A method to assemble light-responsive or pH-responsive microcapsules loaded with different loads (tetramethylrhodamine-modified dextran, TMR-D; microperoxidase-11, MP-11; CdSe/ZnS quantum dots; or doxorubicin-modified dextran, DOX-D) is described. The method is based on the layer-by-layer deposition of sequence-specific nucleic acids on poly(allylamine hydrochloride)-functionalized CaCO3 core microparticles, loaded with the different loads, that after the dissolution of the core particles with EDTA yields the stimuli-responsive microcapsules that include the respective loads. The light-responsive microcapsules are composed of photocleavable o-nitrobenzyl-phosphate-modified DNA shells, and the pH-responsive microcapsules are made of a cytosine-rich layer cross-linked by nucleic acid bridges. Irradiating the o-nitrobenzyl phosphate-functionalized microcapsules, λ = 365 nm, or subjecting the pH-responsive microcapsules to pH = 5.0, results in the cleavage of the microcapsule shells and...
Proceedings of the National Academy of Sciences, 2016
Significance Elevated expression of the iron–sulfur (Fe-S) protein nutrient-deprivation autophagy... more Significance Elevated expression of the iron–sulfur (Fe-S) protein nutrient-deprivation autophagy factor-1 (NAF-1) is associated with the progression of multiple cancer types. Here we demonstrate that the lability of the Fe-S cluster of NAF-1 plays a key role in promoting breast cancer cell proliferation, tumor growth, and resistance of cancer cells to oxidative stress. Our study establishes an important role for the unique 3Cys-1His Fe-S cluster coordination structure of NAF-1 in promoting the development of breast cancer tumors and suggests the potential use of drugs that suppress NAF-1 accumulation or stabilize its cluster in the treatment of cancers that display high expression levels of NAF-1.
An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a bro... more An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance.
Proceedings of the National Academy of Sciences, 2022
Significance Here we address the important question of cross-talk between the mitochondria and cy... more Significance Here we address the important question of cross-talk between the mitochondria and cytosol. We show that the inner mitochondrial protein, MiNT, interacts with a protein on the outer mitochondrial membrane (mNT). This interaction occurs within the major outer membrane protein VDAC1. Inside the inner space of VDAC1, MiNT transfers its [2Fe-2S] clusters to mNT, which was shown to be a [2Fe-2S] cluster donor protein that donates its cluster(s) to apo-acceptor proteins residing in the cytosol. Hence, we suggest a pathway for transferring [2Fe-2S] clusters from inside the mitochondria to the cytosol.
UiO-66 metal–organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahed... more UiO-66 metal–organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahedra provide superior biomarker-responsive hybrid nano-carriers for biomedical applications.
The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and ... more The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and neurodegenerative diseases. It was found to control different calcium, reactive oxygen species (ROS), and iron signaling mechanisms. However, since most studies of CISD2 to date were conducted with cells that constitutively lack, overexpress, or contain mutations in CISD2, the relationships between these different signaling processes are unclear. To address the hierarchy of signaling events occurring in cells upon CISD2 disruption, we developed an inducible system to express CISD2, or the dominant-negative H114C inhibitor of CISD2, in human breast cancer cells. Here, we report that inducible disruption of CISD2 function causes an immediate disruption in mitochondrial labile iron (mLI), and that this disruption results in enhanced mitochondrial ROS (mROS) levels. We further show that alterations in cytosolic and ER calcium levels occur only after the changes in mLI and mROS levels happen and are unrelated to them. Interestingly, disrupting CISD2 function resulted in the enhanced expression of the tumor suppressor thioredoxin-interacting protein (TXNIP) that was dependent on the accumulation of mLI and associated with ferroptosis activation. CISD2 could therefore regulate the expression of TXNIP in cancer cells, and this regulation is dependent on alterations in mLI levels.
The reversible and switchable triggered reconfiguration of tetrahedra nanostructures from monomer... more The reversible and switchable triggered reconfiguration of tetrahedra nanostructures from monomer tetrahedra structures into dimer or trimer structures is introduced. The triggered bridging of monomer tetrahedra by K+‐ion‐stabilized G‐quadruplexes or T‐A•T triplexes leads to dimer or trimer tetrahedra structures that are separated by crown ether or basic pH conditions, respectively. The signal‐triggered dimerization/trimerization of DNA tetrahedra structures is used to develop multiplexed miRNA‐sensing platforms, and the tetrahedra mixture is used for intracellular sensing and imaging of miRNAs.
The sensing modules for analyzing miRNAs or the endonucleases consist of tetrahedra functionalize... more The sensing modules for analyzing miRNAs or the endonucleases consist of tetrahedra functionalized with three different fluorophore-quencher pairs in spatially quenched configurations, and hairpin units acting as recognition elements for the analytes. Three different miRNAs (miRNA-21; miRNA-221 and miRNA-155) or three different endonucleases (Nt.BbvCI; EcoRI and HindIII) uncage the respective hairpins, leading to the switched-on fluorescence of the respective fluorophores and to the multiplex detection of the respective analytes. In addition, a tetrahedron module for the multiplexed analysis of aptamer ligand complexes (ligands = ATP, thrombin, VEGF) is introduced. The module includes edges modified with three spatially separated fluorophore-quencher pairs that were stretched by the respective aptamer strands to yield a switched-on fluorescent state. Formation of the respective aptamer ligands reconfigures the edges into fluorophore-quenched caged-hairpin structures that enable the multiplexed analysis of the aptamer-ligand complexes. The facile permeation of the tetrahedra structures into cells is used for the imaging of MCF-7 and HepG2 cancer cells, and their discrimination from normal epithelial MCF-10A breast cells.
Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic d... more Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito‐C. Mito‐C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito‐C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF‐1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER–mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito‐C counteracts dengue virus‐induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including M...
A method to assemble stimuli-responsive nucleic acid-based hydrogel-stabilized microcapsule-in-mi... more A method to assemble stimuli-responsive nucleic acid-based hydrogel-stabilized microcapsule-in-microcapsule systems is introduced. An inner aqueous compartment stabilized by stimuli-responsive hydrogel-layer (ca. 150 nm) provides the inner microcapsule (diameter ca. 2.5 µm). The inner microcapsule is separated from the outer aqueous compartment stabilized by an outer stimuli-responsive hydrogel layer (thickness of ca. 150 nm) that yields a microcapsule-in-microcapsule system. Different loads, e.g. tetramethyl rhodamine-dextran (TMR-D) and CdSe/ZnS quantum dots (QDs), are loaded in the inner and outer aqueous compartments. The hydrogel layers exist in a higher stiffness state that prevents inter-reservoir or leakage of the loads from the respective aqueous compartments. Subjecting the inner hydrogel layer to Zn 2+ -ion and/or the outer hydrogel layer to acidic pH or crown ether leads to the triggered separation of the bridging units associated with the respective hydrogel layers. This results in hydrogel layers of lower stiffness allowing either the mixing of the loads occupying the two aqueous compartments, the guided release of the load from the outer aqueous compartment, or the release of the loads from the two aqueous compartments. In addition, the pH-responsive microcapsule-in-microcapsule system is loaded with glucose oxidase (GOx) in the inner aqueous compartment and insulin in the outer aqueous compartment. Glucose permeates across the two hydrogel layers resulting in the glucose oxidase catalyzed aerobic oxidation of glucose to gluconic acid. The acidification of the microcapsule-in-microcapsule system leads to the triggered unlocking of the outer, pH-responsive hydrogel layer and to the release of insulin. The pH-stimulated release of insulin is controlled by the concentration of glucose. While at normal glucose levels, the release of insulin is practically prohibited, the dose-controlled release of insulin in the entire concentration range of diabetic concern is demonstrated. Also, switchable ON/OFF release of insulin is achieved highlighting an autonomous glucose-responsive microdevice operating as an "artificial pancreas" for the release of insulin.
Nucleic acid-modified UiO-68 metal-organic framework nanoparticles, NMOFs, are loaded with the an... more Nucleic acid-modified UiO-68 metal-organic framework nanoparticles, NMOFs, are loaded with the anticancer drug camptothecin (or drug models), and the loaded NMOFs are capped with sequence-specific duplex units. The NMOFs are unlocked by the biocatalytic decomposition of the duplex capping units that result in the release of the drug (or drug models). The enzymes used are DNase I, a nicking enzyme (Nt.BbvCI), an endonuclease (EcoRI), and an exonuclease III (Exo III). Camptothecin-loaded NMOFs, capped by tailored hairpin nucleic acids being cooperatively unlocked by adenosine triphosphate (ATP), that is overexpressed in cancer cells, and Exo III are prepared. The camptothecin-loaded NMOFs reveal that selective cytotoxicity toward MDA-MB-231 cancer cells and ≈55% apoptosis of the cancer cells is observed after 5 days of treatment with the NMOFs, while only ≈15% apoptosis of epithelial MCF-10A breast cells is observed.
Nanoparticles consisting of metal–organic frameworks (NMOFs) modified with nucleic acid binding s... more Nanoparticles consisting of metal–organic frameworks (NMOFs) modified with nucleic acid binding strands are synthesized. The NMOFs are loaded with a fluorescent agent or with the anticancer drug doxorubicin, and the loaded NMOFs are capped by hybridization with a complementary nucleic acid that includes the ATP‐aptamer or the ATP‐AS1411 hybrid aptamer in caged configurations. The NMOFs are unlocked in the presence of ATP via the formation of ATP‐aptamer complexes, resulting in the release of the loads. As ATP is overexpressed in cancer cells, and since the AS1411 aptamer recognizes the nucleolin receptor sites on the cancer cell membrane, the doxorubicin‐loaded NMOFs provide functional carriers for targeting and treatment of cancer cells. Preliminary cell experiments reveal impressive selective permeation of the NMOFs into MDA‐MB‐231 breast cancer cells as compared to MCF‐10A normal epithelial breast cells. High cytotoxic efficacy and targeted drug release are observed with the ATP‐...
We reveal a novel interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are ... more We reveal a novel interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are overexpressed in many types of cancer cells, and propose that this interaction is required for apoptosis activation in cancer cells. A peptide derived from the interaction interface inhibits apoptosis in cells.
Zeolitic Zn-imidazolate cross-linked framework nanoparticles, ZIF-8 NMOFs, are used as "smar... more Zeolitic Zn-imidazolate cross-linked framework nanoparticles, ZIF-8 NMOFs, are used as "smart" glucose-responsive carriers for the controlled release of drugs. The ZIF-8 NMOFs are loaded with the respective drug and glucose oxidase (GOx), and the GOx-mediated aerobic oxidation of glucose yields gluconic acid and HO. The acidification of the NMOFs' microenvironment leads to the degradation of the nanoparticles and the release of the loaded drugs. In one sense-and-treat system, GOx and insulin are loaded in the NMOFs. In the presence of glucose, the nanoparticles are unlocked, resulting in the release of insulin. The release of insulin is controlled by the concentration of glucose. In the second sense-and-treat system, the NMOFs are loaded with the antivascular endothelial growth factor aptamer (VEGF aptamer) and GOx. In the presence of glucose, the ZIF-8 NMOFs are degraded, leading to the release of the VEGF aptamer, which acts as a potential inhibitor of the angiogenet...
Cancer cells accumulate high levels of iron and reactive oxygen species (ROS) to promote their hi... more Cancer cells accumulate high levels of iron and reactive oxygen species (ROS) to promote their high metabolic activity and proliferation rate. However, high levels of iron and ROS can also lead to enhanced oxidative stress and the activation of cell death pathways such as apoptosis and ferroptosis. This has led to the proposal that different drugs that target iron and/or ROS metabolism could be used as anticancer drugs. However, due to the complex role iron and ROS play in cells, the majority of these drugs yielded mixed results, highlighting a critical need to identify new players in the regulation of iron and ROS homeostasis in cancer cells. Recent Advances: NEET proteins belong to a newly discovered class of iron-sulfur (2Fe-2S) proteins required for the regulation of iron and ROS homeostasis in cells. Recent studies revealed that the NEET proteins NAF-1 (CISD2) and mitoNEET (CISD1) play a critical role in promoting the proliferation of cancer cells, supporting tumor growth and m...
Proceedings of the National Academy of Sciences of the United States of America, Jan 9, 2018
The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important... more The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased ac...
Drug-loaded DNA-capped metal–organic framework nanoparticles are unlocked by pH or Mg2+ ions/ATP ... more Drug-loaded DNA-capped metal–organic framework nanoparticles are unlocked by pH or Mg2+ ions/ATP triggers, resulting in the release of the loads.
Journal of Chemical Information and Modeling, 2016
Specific iron chelation is a validated strategy in anticancer drug discovery. However, only a few... more Specific iron chelation is a validated strategy in anticancer drug discovery. However, only a few chemical classes (4-5 categories) have been reported to date. We discovered in silico 5 new structurally diverse iron chelators by screening through models based on previously known chelators. To encompass a larger chemical space and propose newer scaffolds, we used our Iterative Stochastic Elimination (ISE) algorithm for model building and subsequent virtual screening (VS). The ISE models were developed by training a dataset of 130 reported iron chelators. The developed models are statistically significant with area under the receiver operating curve greater than 0.9. The models were used to screen the Enamine chemical database of ~1.8 million molecules. The top ranked 650 molecules were reduced to 50 diverse structures, and a few others were eliminated due to the presence of reactive groups. Finally, 34 molecules were purchased and tested in vitro. Five compounds were identified with significant iron chelation activity in Cal-G assay. Intracellular iron-chelation study revealed one compound as equivalent in potency to the iron chelating "gold standards" DFO and DFP. The amount of discovered positives (5 out of 34) is expected by the realistic enrichment factor of the model.
Journal of the American Chemical Society, Jul 20, 2016
A method to assemble light-responsive or pH-responsive microcapsules loaded with different loads ... more A method to assemble light-responsive or pH-responsive microcapsules loaded with different loads (tetramethylrhodamine-modified dextran, TMR-D; microperoxidase-11, MP-11; CdSe/ZnS quantum dots; or doxorubicin-modified dextran, DOX-D) is described. The method is based on the layer-by-layer deposition of sequence-specific nucleic acids on poly(allylamine hydrochloride)-functionalized CaCO3 core microparticles, loaded with the different loads, that after the dissolution of the core particles with EDTA yields the stimuli-responsive microcapsules that include the respective loads. The light-responsive microcapsules are composed of photocleavable o-nitrobenzyl-phosphate-modified DNA shells, and the pH-responsive microcapsules are made of a cytosine-rich layer cross-linked by nucleic acid bridges. Irradiating the o-nitrobenzyl phosphate-functionalized microcapsules, λ = 365 nm, or subjecting the pH-responsive microcapsules to pH = 5.0, results in the cleavage of the microcapsule shells and...
Proceedings of the National Academy of Sciences, 2016
Significance Elevated expression of the iron–sulfur (Fe-S) protein nutrient-deprivation autophagy... more Significance Elevated expression of the iron–sulfur (Fe-S) protein nutrient-deprivation autophagy factor-1 (NAF-1) is associated with the progression of multiple cancer types. Here we demonstrate that the lability of the Fe-S cluster of NAF-1 plays a key role in promoting breast cancer cell proliferation, tumor growth, and resistance of cancer cells to oxidative stress. Our study establishes an important role for the unique 3Cys-1His Fe-S cluster coordination structure of NAF-1 in promoting the development of breast cancer tumors and suggests the potential use of drugs that suppress NAF-1 accumulation or stabilize its cluster in the treatment of cancers that display high expression levels of NAF-1.
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Papers by Yang Sung Sohn