Shumei Zhai

Design, Synthesis, Cytoselective Toxicity, Structure-Activity Relationships, and Pharmacophore of Thiazolidinone Derivatives Targeting Drug-Resistant Lung Cancer Cells

Ten cytoselective compounds have been identified from 372 thiazolidinone analogues by applying iterative library approaches. These compounds selectively killed both non-small cell lung cancer cell line H460 and its paclitaxel-resistant variant H460 taxR at an IC 50 between 0.21 and 2.93 microM while showing much less toxicity to normal human fibroblasts at concentrations up to 195 microM. Structure-activity relationship studies revealed that (1) the nitrogen atom on the 4-thiazolidinone ring (ring B in Figure 1) cannot be substituted, (2) several substitutions on ring A are tolerated at various positions, and (3) the substitution on ring C is restricted to the -NMe 2 group at the 4-position. A pharmacophore derived from active molecules suggested that two hydrogen bond acceptors and three hydrophobic regions were common features. Activities against P-gp-overexpressing and paclitaxel-resistant cell line H460 taxR and modeling using a previously validated P-gp substrate pharmacophore suggested that active compounds were not likely P-gp substrates.

Tuning Cell Autophagy by Diversifying Carbon Nanotube Surface Chemistry

The induction of autophagy by nanoparticles causes nanotoxicity, but appropriate modulation of autophagy by nanoparticles may have therapeutic potential. Multiwalled carbon nanotubes (MWCNTs) interact with cell membranes and membrane-associated molecules before and after internalization. These interactions alter cellular signaling and impact major cell functions such as cell cycle, apoptosis, and autophagy. In this work, we demonstrated that MWCNT-cell interactions can be modulated by varying densely distributed surface ligands on MWCNTs. Using a fluorescent autophagy-reporting cell line, we evaluated the autophagy induction capability of 81 surface-modified MWCNTs. We identified strong and moderate autophagy-inducing MWCNTs as well as those that did not induce autophagy. Variation of the surface ligand structure of strong autophagy nanoinducers led to the induction of different autophagy-activating signaling pathways, presumably through their different interactions with cell surface receptors.

Natural Product-Inspired Synthesis of Thiazolidine and Thiazolidinone Compounds and their Anticancer Activities

Nature makes many pharmacologically active compounds containing thiazolidine and thiazolidinone scaffolds. These privileged structures have been identified in many random screening assays. Molecules containing these core structures have been designed and synthesized, and they show a broad range of anticancer activities in vitro and in vivo. The combinatorial library approach has been demonstrated to be effective in lead discovery and optimization in order to improve the potency and toxicity of these compounds.

Induction of Size-Dependent Breakdown of Blood-Milk Barrier in Lactating Mice by TiO2 Nanoparticles

This study aims to investigate the potential nanotoxic effects of TiO2 nanoparticles (TNPs) to dams and pups during lactation period. TiO2 nanoparticles are accumulated in mammary glands of lactating mice after i.v. administration. This accumulation of TiO2 NP likely causes a ROS-induced disruption of tight junction of the blood-milk barrier as indicated by the loss of tight junction proteins and the shedding of alveolar epithelial cells. Compared to larger TNPs (50 nm), smaller ones (8 nm) exhibit a higher accumulation in mammary glands and are more potent in causing perturbations to blood-milk barrier. An alarming finding is that the smaller TNPs (8 nm) are transferred from dams to pups through breastfeeding, likely through the disrupted blood-milk barrier. However, during the lactation period, the nutrient quality of milk from dams and the early developmental landmarks of the pups are not affected by above perturbations.

Anti-tumor selectivity of a novel tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models.

Dose-limiting toxicity is a main road blocker for successful cancer chemotherapy. By phenotype screening, a novel chemical agent 2-(2-Chlorophenylimino)-5-(4-dimethylamino-benzylidene) thiazolidin-4-one (CDBT) was found to strongly inhibit the proliferation of non-small cell lung cancer (NSCLC) cells H460 and H322 while displaying no obvious toxicity to normal fast-dividing fibroblast cells NHFB and WI-38 at a concentration 100-fold higher than its EC50 to NSCLC cells. CDBT targets microtubule and heat shock protein 90 (HSP90) simultaneously with moderate affinities compared to microtubule targeting Colchicine and HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygaldanamcyin (17-DMAG). CDBT blocks microtubule formation, decreases cancer-essential proteins CRAF-1, ERBB2 and phosphorylated AKT, and causes G2/M arrest and apoptosis. The moderate inhibitory effects of CDBT on targets require a higher cellular concentration of targets, a situation only exist in cancer cells. This accounts for its good cancer selectivity. Furthermore, CDBT effectively inhibits tumor growth by 62.4% relative to the vehicle control after i.p. administration at 30 mg/kg for 11 days while showing no toxicity to normal tissues in NSCLC H460 xenograft mouse model.

Cell Rescue by Nanosequestration: Reduced Cytotoxicity of An Environmental Remediation Residue, Mg(OH)(2) Nanoflake/Cr(VI) Adduct

Some nanomaterials, such as Mg(OH)2 nanoflakes, are heavily used in pollutant adsorption and removal. Residues from these environmental remediations are potential hazardous materials. Safety evaluations of these materials are needed for environmental protection and human health. Although nanotoxicity has been widely investigated in recent years, research on the toxicity of nanoparticle/pollutant adducts has been rather inadequate. Here, we report the cellular perturbations and cytotoxicity of nano-Mg(OH)2/Cr(VI) adducts as a case study to elucidate how nanoparticle/pollutant adducts impact human cells. We found that Mg(OH)2 nanoflakes barely enter cells, while desorbed Cr(VI) anions enter cells, generate ROS, induce cell apoptosis, and cause cytotoxicity. This cytotoxicity is only a fraction of the cytotoxicity of free Cr(VI) because nano-Mg(OH)2 particles are able to retain more than half of their Cr(VI) anions.

Novel Natural Product- and Privileged Scaffold-Based Tubulin Inhibitors Targeting the Colchicine Binding Site.

Tubulin inhibitors are effective anticancer agents, however, there are many limitations to the use of available tubulin inhibitors in the clinic, such as multidrug resistance, severe side-effects, and generally poor bioavailability. Thus, there is a constant need to search for novel tubulin inhibitors that can overcome these limitations. Natural product and privileged structures targeting tubulin have promoted the discovery and optimization of tubulin inhibitors. This review will focus on novel tubulin inhibitors derived from natural products and privileged structures targeting the colchicine binding site on tubulin.

Experimental modulation and computational model of nano-hydrophobicity

We demonstrate that nano-hydrophobicity, which governs the biological aggressiveness of nanoparticles, is determined by the outermost regions of surface ligands. We have also successfully modulated nano-hydrophobicity using systematic surface ligand modifications and built the first computational model of nano-hydrophobicity.

Adsorption of bisphenol A to a carbon nanotube reduced its endocrine disrupting effect in mice male offspring.

Soluble carbon nanotubes (CNTs) have shown promise as materials for adsorption of environmental contaminants such as Bisphenol A (BPA), due to the high adsorption capacity and strong desorption hysteresis of BPA on CNTs. The adsorption of BPA to CNTs may change the properties of both BPA and CNTs, and induce different toxicity to human and living systems from that of BPA and CNTs alone. Herein, we report that oral exposure of BPA/MWCNT–COOH (carboxylated multi-walled carbon nantubes) adduct to mice during gestation and lactation period decreased the male offspring reproductive toxicity compared with those induced by BPA alone. The adduct decreased malondialdehyde (MDA) level in testis and follicle-stimulating hormone (FSH) in serum, but increased the level of serum testosterone in male offspring in comparison to BPA alone. Our investigations broadened the knowledge of nanotoxicity and provided important information on the safe application of CNTs.

Synergistic action by multi-targeting compounds produces a potent compound combination for human NSCLC both in vitro and in vivo

By screening a collection of one hundred combinations of thiazolidinone compounds, we identified one combination (M4) that synergistically inhibited the growth of H460 and H460/TaxR cells and tumor growth in H460/TaxR xenograft mice. A whole genome microarray assay showed that genes involved in negative regulation of microtubule polymerization or depolymerization, intracellular protein kinase cascade, positive regulation of histone acetylation, cell cycle arrest and apoptosis were upregulated. Further analysis proved that the four compounds act as either microtubule polymerization inhibitors or histone deacetylase inhibitors. They act synergistically targeting multiple proteins and leading to the regulation of cell cycle checkpoint proteins, including p53, p21, cdc25C and cdc2, the activation of caspases, JNK, p38 cascades and the inactivation of Akt. These events resulted in the G2/M cell cycle arrest and cell apoptosis. These data provide a new strategy for discovering anticancer drugs and drug combinations for drug-resistant cancers.