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Heat shock protein 90 (Hsp90) is a promising cancer drug target, as multiple oncogenic proteins are destabilized simultaneously when it loses its activity in tumor cells. Highly selective Hsp90 inhibitors, including the natural antibiotics geldanamycin (GdA) and radicicol (RAD), inactivate this essential molecular chaperone by occupying its nucleotide binding site. Often cancer drug therapy is compromised by the development of resistance, but a resistance to these Hsp90 inhibitors should not arise readily by mutation of those amino acids within Hsp90 that facilitate inhibitor binding, as these are required for the essential ATP binding/ATPase steps of the chaperone cycle and are tightly conserved. Despite this, the Hsp90 of a RAD-producing fungus is shown to possess an unusually low binding affinity for RAD but not GdA. Within its nucleotide binding site a normally conserved leucine is replaced by isoleucine, though the chaperone ATPase activity is not severely affected. Inserted into the Hsp90 of yeast, this conservative leucine to isoleucine substitution recreated this lowered affinity for RAD in vitro. It also generated a substantially enhanced resistance to RAD in vivo. Co-crystal structures reveal that the change to isoleucine is associated with a localized increase in the hydration of an Hsp90-bound RAD but not GdA. To the best of our knowledge, this is the first demonstration that it is possible for Hsp90 inhibitor resistance to arise by subtle alteration to the structure of Hsp90 itself.
ACS Chem Biol 2009 Apr 17
PMID:Structural basis of the radicicol resistance displayed by a fungal hsp90. 1923 53

Silver nanoparticles (Ag-np) are being used increasingly in wound dressings, catheters, and various household products due to their antimicrobial activity. The toxicity of starch-coated silver nanoparticles was studied using normal human lung fibroblast cells (IMR-90) and human glioblastoma cells (U251). The toxicity was evaluated using changes in cell morphology, cell viability, metabolic activity, and oxidative stress. Ag-np reduced ATP content of the cell caused damage to mitochondria and increased production of reactive oxygen species (ROS) in a dose-dependent manner. DNA damage, as measured by single cell gel electrophoresis (SCGE) and cytokinesis blocked micronucleus assay (CBMN), was also dose-dependent and more prominent in the cancer cells. The nanoparticle treatment caused cell cycle arrest in G(2)/M phase possibly due to repair of damaged DNA. Annexin-V propidium iodide (PI) staining showed no massive apoptosis or necrosis. The transmission electron microscopic (TEM) analysis indicated the presence of Ag-np inside the mitochondria and nucleus, implicating their direct involvement in the mitochondrial toxicity and DNA damage. A possible mechanism of toxicity is proposed which involves disruption of the mitochondrial respiratory chain by Ag-np leading to production of ROS and interruption of ATP synthesis, which in turn cause DNA damage. It is anticipated that DNA damage is augmented by deposition, followed by interactions of Ag-np to the DNA leading to cell cycle arrest in the G(2)/M phase. The higher sensitivity of U251 cells and their arrest in G(2)/M phase could be explored further for evaluating the potential use of Ag-np in cancer therapy.
ACS Nano 2009 Feb 24
PMID:Cytotoxicity and genotoxicity of silver nanoparticles in human cells. 1923 62

Carbon nanotube-based drug delivery holds great promise for cancer therapy. Herein we report the first targeted, in vivo killing of cancer cells using a drug-single wall carbon nanotube (SWNT) bioconjugate, and demonstrate efficacy superior to nontargeted bioconjugates. First line anticancer agent cisplatin and epidermal growth factor (EGF) were attached to SWNTs to specifically target squamous cancer, and the nontargeted control was SWNT-cisplatin without EGF. Initial in vitro imaging studies with head and neck squamous carcinoma cells (HNSCC) overexpressing EGF receptors (EGFR) using Qdot luminescence and confocal microscopy showed that SWNT-Qdot-EGF bioconjugates internalized rapidly into the cancer cells. Limited uptake occurred for control cells without EGF, and uptake was blocked by siRNA knockdown of EGFR in cancer cells, revealing the importance of EGF-EGFR binding. Three color, two-photon intravital video imaging in vivo showed that SWNT-Qdot-EGF injected into live mice was selectively taken up by HNSCC tumors, but SWNT-Qdot controls with no EGF were cleared from the tumor region in <20 min. HNSCC cells treated with SWNT-cisplatin-EGF were also killed selectively, while control systems that did not feature EGF-EGFR binding did not influence cell proliferation. Most significantly, regression of tumor growth was rapid in mice treated with targeted SWNT-cisplatin-EGF relative to nontargeted SWNT-cisplatin.
ACS Nano 2009 Feb 24
PMID:Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. 1923 65

In this paper, we report the successful use of non-cadmium-based quantum dots (QDs) as highly efficient and nontoxic optical probes for imaging live pancreatic cancer cells. Indium phosphide (core)-zinc sulfide (shell), or InP/ZnS, QDs with high quality and bright luminescence were prepared by a hot colloidal synthesis method in nonaqueous media. The surfaces of these QDs were then functionalized with mercaptosuccinic acid to make them highly dispersible in aqueous media. Further bioconjugation with pancreatic cancer specific monoclonal antibodies, such as anticlaudin 4 and antiprostate stem cell antigen (anti-PSCA), to the functionalized InP/ZnS QDs, allowed specific in vitro targeting of pancreatic cancer cell lines (both immortalized and low passage ones). The receptor-mediated delivery of the bioconjugates was further confirmed by the observation of poor in vitro targeting in nonpancreatic cancer based cell lines which are negative for the claudin-4-receptor. These observations suggest the immense potential of InP/ZnS QDs as non-cadmium-based safe and efficient optical imaging nanoprobes in diagnostic imaging, particularly for early detection of cancer.
ACS Nano 2009 Mar 24
PMID:Imaging pancreatic cancer using bioconjugated InP quantum dots. 1924 45

Normal growth and development depends upon high fidelity regulation of cap-dependent translation initiation, a process that is usurped and redirected in cancer to mediate acquisition of malignant properties. The epithelial-to-mesenchymal transition (EMT) is a key translationally regulated step in the development of epithelial cancers and pathological tissue fibrosis. To date, no compounds targeting EMT have been developed. Here we report the synthesis of a novel class of histidine triad nucleotide binding protein (HINT)-dependent pronucleotides that interdict EMT by negatively regulating the association of eIF4E with the mRNA cap. Compound eIF4E inhibitor-1 potently inhibited cap-dependent translation in a dose-dependent manner in zebrafish embryos without causing developmental abnormalities and prevented eIF4E from triggering EMT in zebrafish ectoderm explants without toxicity. Metabolism studies with whole cell lysates demonstrated that the prodrug was rapidly converted into 7-BnGMP. Thus we have successfully developed the first nontoxic small molecule able to inhibit EMT, a key process in the development of epithelial cancer and tissue fibrosis, by targeting the interaction of eIF4E with the mRNA cap and demonstrated the tractability of zebrafish as a model organism for studying agents that modulate EMT. Our work provides strong motivation for the continued development of compounds designed to normalize cap-dependent translation as novel chemo-preventive agents and therapeutics for cancer and fibrosis.
ACS Chem Biol 2009 May 15
PMID:Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation. 1935 Nov 81

Nanoparticles have shown tremendous potential for effective drug delivery due to their tiny size and cell membrane penetration capabilities. Cellular targeting with nanoparticles is often achieved by surface modifications followed by ligand conjugation. However, the efficiency of the nanoparticles reaching the target cells and getting internalized depends on the stability of targeting ligands and the chemical nature of the ligand nanoparticle binding. Recent advancements in nanobiomaterials research have proven the superoxide dismutase (SOD) mimetic activity of cerium oxide nanoparticles (CNPs) in protecting cells against oxidative stress. Due to their excellent biocompatibility, CNPs can be used as a potential drug carrier that can transport and release drugs to the malignant sites. Here we combine single molecule force spectroscopy (SMFS) and density functional theory (DFT) simulations to understand the interaction between transferrin, a ligand protein overexpressed in cancer cells, and CNPs. SMFS studies demonstrate an increase in the transferrin adhesion to the nanoparticles' surface with an increase in positive zeta potential of CNPs. Binding energy values obtained from DFT calculations predict an increase in bond strength between the transferrin and CNPs upon surface protonation and charge modification. Transferrin-conjugated CNPs were tested for their binding stability and preferential cellular uptake efficiency by incubating them with human lung cancer cells (A549) and normal embryo lung cells (WI-38). The results demonstrate the importance of tuning the surface properties of nanoparticles for better ligand adsorption and cellular uptake.
ACS Nano 2009 May 26
PMID:Protonated nanoparticle surface governing ligand tethering and cellular targeting. 1936 74

Resistance to Hsp90 inhibition has become an important concern as several clinical trials are currently in progress for the treatment of cancer. A summary of known mechanisms of resistance to Hsp90 inhibitors is provided, including the recent solution of the Humicola fuscoatra Hsp90 structure, the organism responsible for the biosynthesis of radicicol. Through careful analyses of Hsp90 structures, a plausible mechanism for resistance to Hsp90 inhibitors has been obtained by single mutations about the N-terminal ATP-binding site.
ACS Chem Biol 2009 Apr 17
PMID:Hydrating for resistance to radicicol. 1937 Nov 33

Understanding tumor-specific metabolism under hypoxia is important to find novel targets for antitumor drug design. Here we found that tumor cells expressed higher levels of cytosolic acetyl-CoA synthetase (ACSS2) under hypoxia than normoxia. Knockdown of ACSS2 by RNA interference (RNAi) in tumor cells enhanced tumor cell death under long-term hypoxia in vitro. Our data also demonstrated that the ACSS2 suppression slowed tumor growth in vivo. These findings showed that ACSS2 plays a significant role in tumor cell survival under hypoxia and that ACSS2 would be a potential target for tumor treatment. Furthermore, we found that tumor cells excreted acetate and the quantity increased under hypoxia: the pattern of acetate excretion followed the expression pattern of ACSS2. Additionally, the ACSS2 knockdown led to a corresponding reduction in the acetate excretion in tumor cells. These results mean that ACSS2 can conduct the reverse reaction from acetyl-CoA to acetate in tumor cells, which indicates that ACSS2 is a bi-directional enzyme in tumor cells and that ACSS2 might play a buffering role in tumor acetyl-CoA/acetate metabolism.
Cancer Sci 2009 May
PMID:Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. 1944 15

The literature covering neurotensin (NT) and its signalling pathways, receptors, and biological profile is complicated by the fact that the discovery of three NT receptor subtypes has come to light only in recent years. Moreover, a lot of this literature explores NT in the context of the central nervous system and behavioral studies. However, there is now good evidence that the up-regulation of NT is intimately involved in cancer development and progression. This Review aims to summarize the isolation, cloning, localization, and binding properties of the accepted receptor subtypes (NTR1, NTR2, and NTR3) and the molecules known to bind at these receptors. The growing role these targets are playing in cancer research is also discussed. We hope this Review will provide a useful overview and a one-stop resource for new researchers engaged in this field at the chemistry-biology interface.
ACS Chem Biol 2009 Jul 17
PMID:Cancer, chemistry, and the cell: molecules that interact with the neurotensin receptors. 1946 83

Upconversion fluorescent nanoparticles can convert a longer wavelength radiation (e.g., near-infrared light) into a shorter wavelength fluorescence (e.g., visible light) and thus have emerged as a new class of fluorescent probes for biomedical imaging. Rare-earth doped beta-NaYF(4):Yb,Er upconversion nanoparticles (UCNPs) with strong UC fluorescence were synthesized in this work by using a solvothermal approach. The UCNPs were coated with a thin layer of SiO(2) to form core-shell nanoparticles via a typical Stober method, which were further modified with amino groups. After surface functionalization, the rabbit anti-CEA8 antibodies were covalently linked to the UCNPs to form the antibody-UCNP conjugates. The antibody-UCNP conjugates were used as fluorescent biolabels for the detection of carcinoembryonic antigen (CEA), a cancer biomarker expressed on the surface of HeLa cells. The successful conjugation of antibody to the UCNPs was found to lead to the specific attachment of the UCNPs onto the surface of the HeLa cells, which further resulted in the bright green UC fluorescence from the UCNP-labeled cells under 980 nm near-infrared (NIR) excitation and enabled the fluorescent imaging and detection of the HeLa cells. These results indicate that the amino-functionalized UCNPs can be used as fluorescent probes in cell immunolabeling and imaging. Because the UCNPs can be excited with a NIR light to exhibit strong visible fluorescence and the NIR light is safe to the body and can penetrate tissue as deep as several inches, our work suggests that, with proper cell-targeting or tumor-homing peptides or proteins conjugated, the NaYF(4):Yb,Er UCNPs can find potential applications in the in vivo imaging, detection, and diagnosis of cancers.
ACS Nano 2009 Jun 23
PMID:Immunolabeling and NIR-excited fluorescent imaging of HeLa cells by using NaYF(4):Yb,Er upconversion nanoparticles. 1947 17


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