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Supermolecularly assembled photochemotherapeutic nanocomposites composed of pure drug small molecules are promising for synergistically improved tumor therapy, yet potential multiple challenges remain to be addressed. Herein, we rationally designed a novel multifunctional small molecule disulfide modified natural pentacyclic triterpene of ursolic acid (UASS) that simultaneously possesses self-assembly ability, glutathione (GSH) responsivity, anticancer activity, biocompatibility and biodegradability and further constructed carrier-free GSH-sensitive photosensitive nanocomposite UASS-Ce6 NPs for safe and synergistically improved chemophototherapy. Specifically, UASS-Ce6 NPs exhibit improved 1O2 generation by reducing the energy gap (ΔEST) of Ce6 as determined by density functional theory. Meanwhile, molecular dynamics simulation revealed the possible reasons why free UASS self-assembles and UASS-Ce6 NPs with different assembled morphologies may be primarily attributed to the coplanar arrangement of UASS dimer units. Importantly, via noncovalent π-stacking and hydrophobic interactions, the resulting co-assemblies showed improved water solubility, increased intercellular ROS generation, desirable GSH sensibility, excellent biocompatibility, and enhanced tumor accumulation accompanied by rapid biodegradation, thus leading to significant in vitro and in vivo synergistic antitumor efficacy with favorable biosafety. This study provides a promising insight into the development of a self-assembled active single component platform with desirable stimuli responsiveness and biosafety toward synergistic antitumor therapy based on terpenoid natural small molecules.

Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria targeting micelle (PEG-AIE-TPP) by conjugating a triphenylphosphonium (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). At first, the in vitro and in vivo properties of the PEG-AIE-TPP micelle were characterized in detail. It was found that the micelle was reasonably stable at physiological pH and highly sensitive to mildly acidic pH stimuli. Importantly, this micelle could selectively localize and accumulate in the mitochondria, thus generating an aggregation-induced emission (AIE) effect as confirmed by the green fluorescence. Additionally, the micelle exhibited selective cytotoxicity to cancer cells and negligible toxicity to normal cells in vitro. The in vivo imaging and ex vivo imaging results showed that the accumulation tendency of the micelle at the tumor region was obvious. We also further proved the biocompatible, tumor targeting ability and antitumor activity of the PEG-AIE-TPP micelle in MCF-7 tumor-bearing mice. Accordingly, this mitochondria-targeted therapeutic micelle with good stability, biocompatibility, and tumor-targeting and antitumor activity provides a potentially unique tumor-targeted system for cancer therapy.

Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.

Curcumin (diferuloylmethane) is a polyphenol natural product of the plant Curcuma longa, and has a diversity of antitumor activities. However, the clinical application of curcumin remains limited due to its poor pharmacokinetic characteristics. It is therefore critical to develop structural analogues of curcumin with increasing anticancer activity. T63, a new 4-arylidene curcumin analogue, was synthesized in our previous studies and exhibited higher in vitro and in vivo anti-tumor activities compared to curcumin. However, the precise molecular mechanism of its anti-tumor effects has not been well elucidated. Using a two-dimensional gel electrophoresis (2-DE)-based proteomic approach, we identified 66 differentially expressed proteins. Similarly to curcumin, T63 showed a diverse range of molecular targets. We proposed that induction of ROS generation and mitochondrial dysfunction, inhibition of proteasome, HSP90, and 14-3-3 proteins play important roles in T63-induced cell cycle arrest and apoptosis. These data indicate that the novel curcumin analogue T63 is a potent anti-tumor agent, which can induce cell cycle arrest and apoptosis, and also provided valuable resources for further study of the anti-tumor effects and molecular mechanisms of T63.

ErbB2 is frequently activated in tumors, and influences a wide array of cellular functions, including proliferation, apoptosis, cell motility and adhesion. HKI-272 (neratinib) is a small molecule pan-kinase inhibitor of the ErbB family of receptor tyrosine kinases, and shows strong antiproliferative activity in ErbB2-overexpressing breast cancer cells. We undertook a genome-wide pooled lentiviral RNAi screen to identify synthetic lethal or enhancer (synthetic modulator screen) genes that interact with neratinib in a human breast cancer cell line (SKBR-3). These genes upon knockdown would modulate cell viability in the presence of subeffective concentrations of neratinib. We discovered a diverse set of genes whose depletion selectively impaired or enhanced the viability of SKBR-3 cells in the presence of neratinib. We observed diverse pathways including EGFR, hypoxia, cAMP, and protein ubiquitination that, when co-treated with RNAi and neratinib, resulted in arrest of cell proliferation. Examining the changes of these genes and their protein products also led to a rationale for clinically relevant drug combination treatments. Treatment of cells with either paclitaxel or cytarabine in combination with neratinib resulted in a strong antiproliferative effect. The identification of novel mediators of cellular response to neratinib and the development of potential drug combination treatments have expanded our understanding of neratinib's mode-of-action for the development of more effective therapeutic regimens. Notably, our findings support a paclitaxel and neratinib phase III clinical trial in breast cancer patients.

Three new lanthanide complexes with dihalo-substituted 8-quinolinol: [Gd(BrQ)(3)(H(2)O)(2)]·1.33EtOH·0.33H(2)O (1), [Dy(ClQ)(3)(H(2)O)(2)]·1.33EtOH·0.33H(2)O (2), [Er(ClQ)(3)(H(2)O)(2)]·1.33EtOH·0.33H(2)O (3) (H-BrQ = 5,7-dibromo-8-quinolinol, H-ClQ = 5,7-dichloro-8-quinolinol) have been synthesized and characterized by elemental analysis, IR, ESI-MS, single-crystal X-ray diffraction and TGA. The single-crystal X-ray diffraction analyses reveal that complexes 1-3 are mononuclear and isostructural. Each metal centre is coordinated by three dihalo-substituted 8-quinolinol and two aqua ligands. The in vitro cytotoxicity of dihalo-substituted 8-quinolinol and complexes 1-3 against liver cancer BEL7404 was evaluated. The IC(50) values of 1-3 to BEL7404 were 47.2 ± 2.6, 18.3 ± 1.0 and 31.5 ± 1.2 nM, respectively. The lanthanide complexes 1-3 exhibited significantly enhanced cytotoxicity vs. free substituted 8-quinolinol. The binding properties of dihalo-substituted 8-quinolinol and complexes 1 and 2 to DNA were investigated by UV-vis, fluorescence, CD spectroscopy and viscosity measurements, as well as agarose gel electrophoresis experiments. Both complexes 1 and 2 interact more strongly with DNA than the free quinolinol ligand. Intercalation is the most probable binding mode for both the complexes and the quinolinol ligands.

Liriodenine (), an active component of the anticancer traditional Chinese medicine (TCM), was isolated from Zanthoxylum nitidum. Its reactions with Pt(II) and Ru(II) afforded three metal complexes: cis-[PtCl2(L)] (), cis-[PtCl2(L)(DMSO)] (), and cis-[RuCl2(L)(DMSO)2].1.5H2O (), the crystal structures of , and were determined by single-crystal X-ray diffraction methods. These complexes were fully characterized by elemental analysis, IR spectrophotometry, 1H and 13C NMR spectroscopies, and ES mass spectrometry. The in vitro cytotoxicity of and complexes against 11 human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. free , suggesting that these compounds display synergy in the combination of metal ions and liriodenine. The binding properties of and its complexes to ct-DNA were investigated through UV-vis, fluorescence, CD spectra, viscosity and agarose gels electrophoretic measurements.

The copper(ii) complexes of tryptanthrin (Try) and 8-bromo-tryptanthrin (BrTry), [CuII(Try)2Cl2] (Try-Cu) and [CuII(BrTry)2Cl2] (BrTry-Cu), were synthesized and fully characterized by spectroscopic methods and single-crystal X-ray diffraction analysis. The copper(ii) centers in the Try-Cu and BrTry-Cu complexes adopted an approximately six-coordinated distorted octahedral geometry. The anticancer activities of Try-Cu and BrTry-Cu were evaluated in vitro against four human cancer cell lines (BEL-7402, T-24, MGC80-3, and HepG2 cells) and one normal human liver cell line (HL-7702 cells). It was found that Try-Cu exhibited selective cytotoxicity against the four selected cancer cells (IC50 = 4.02–9.03 μM) but low cytotoxicity toward the normal human liver HL-7702 cells. Further studies revealed that Try-Cu exhibited its cytotoxic activity mainly by inducing DNA damage and thus causing cell cycle arrest in the S phase, as well as stimulating mitochondrial dysfunction and inhibiting telomerase by interacting with the c-myc promoter. [ABSTRACT FROM AUTHOR]

Complexes of yttrium(iii) and dysprosium(iii) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex 2 effectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin. [ABSTRACT FROM AUTHOR]