Fung-Ming Siu

Metal complexes in medicine with a focus on enzyme inhibition.

Since the clinical success of cisplatin and its derivatives, considerable effort has been expended by academics and pharmacological companies to the development of novel metal-based drugs. DNA is believed to be the main target of cisplatin, and there have been extensive studies on the binding between metal complexes and DNA targets. Recently, new light has been shed on the discovery of metal-based drugs that inhibit enzymatic activities or even target proteins directly. This review highlights some exciting results published recently on the development of platinum, gold, and ruthenium complexes as enzyme inhibitors for potential therapeutic applications.

Proteomic and transcriptomic study on the action of a cytotoxic saponin (Polyphyllin D): Induction of endoplasmic reticulum stress and mitochondria‐mediated apoptotic pathways

Polyphyllin D (PD) is a potent cytotoxic saponin found in Paris polyphylla. In the present study, bioinformatic, proteomic and transcriptomic analyses were performed to study the mechanisms of action of PD on human nonsmall cell lung cancer (NSCLC) cell line (NCI‐H460). Using a gene expression‐based bioinformatic tool (connectivity map), PD was identified as a potential ER stress inducer. Our proteomic and transcriptomic analyses revealed that PD treatment led to upregulation of typical ER stress‐related proteins/genes including glucose‐regulated protein 78 (BiP/GRP78) and protein disulfide isomerase (PDI). In particular, elevated expression of C/EBP homologous transcription factor (chop) and activation of caspase‐4 occurred at early time point (8 h) of PD treatment, signifying an initial ER stress‐mediated apoptosis. Induction of tumor suppressor p53, disruption of mitochondrial membrane, activation of caspase‐9 and caspase‐3 were detected upon prolonged PD treatment. Collectively, these data revealed that PD induced the cytotoxic effect through a mechanism initiated by ER stress followed by mitochondrial apoptotic pathway. The ability of activating two major pathways of apoptosis makes PD an attractive drug lead for anticancer therapeutics.

Anticancer gold(I)–phosphine complexes as potent autophagy-inducing agents

A panel of anticancer gold(I)-phosphine complexes exhibit significant autophagy-inducing properties in cancer cells.

A novel mechanism of XIAP degradation induced by timosaponin AIII in hepatocellular carcinoma.

Inducing tumor cell death is one of the major therapeutic strategies in treating cancer. The aim of this study is to investigate the mechanism underlying the involvement of autophagy in cell death induced by timosaponin AIII (TAIII). Cell viability was determined by MTT and cologenic assay; apoptosis was determined by flow cytometry and TUNEL assay; autophagy was examined by immunoblotting and immunofluorescence; ubiquitination was detected by co-immunoprecipitation; mRNA expression was detected by real-time PCR; and determination of necrotic cell death was approached with LDH assay. The in vivo tumor growth inhibition was determined by xenograft model. TAIII exhibits potent cytotoxicity on human hepatocellular carcinoma (HCC) cells without severe hepatic toxicity. TAIII induced caspase-dependent apoptosis in HCC, and the induction of apoptosis was attributed to the inhibition of TAIII on XIAP expression. Repressing XIAP expression allowed cell tolerance toward the treatment with TAIII. The suppression of XIAP by TAIII is under post-transcriptional control and independent of proteasomal-driven proteolysis. Instead, TAIII-induced AMPKα/mTOR-dependent autophagy was responsible for XIAP suppression and triggered the XIAP heading lysosomal degradation pathway. Ubiquitination of IAPs is required for the autophagic degradation induced by TAIII. Blockade of autophagy turns on the switch of necrotic cell death in TAIII-treated cells. Timosaponin AIII induces HCC cell apoptosis through a p53-independent mechanism involving XIAP degradation through autophagy-lysosomal pathway. The possibility of developing TAIII as a new anti-tumor agent is worth considering.

Anticancer dirhodium(ii,ii) carboxylates as potent inhibitors of ubiquitin-proteasome system

Dirhodium(II,II) carboxylates are documented to exhibit both in vitro and in vivo anticancer properties. In literatures, DNA is a proposed molecular target of anticancer active dirhodium(II,II) compounds. Herein, we provide compelling evidences that for the dirhodium(II,II) carboxylates examined in this work (Rh2L4, where L = μ2-OOCMe RhA, μ2-OOCnPr RhB, μ2-OOCiBu RhIsoVal, μ2-OOCiPr RhIsoButyl, μ2-OOCC2H4COPh RhPCOPh or μ2-OOCC3H6COPh RhBCOPh), a prominent mechanism of action is the inhibition of ubiquitin–proteasome system (UPS). Using an unbiased connectivity map analysis, the changes in global gene expression upon treatment of cells with dirhodium(II,II) acetate and butyrate are similar to that of proteasome inhibitors. Cellular studies revealed that dirhodium(II,II) butyrate at submicromolar concentrations exerts a strong inhibition of UPS, attributable to impairment of proteasomal proteolysis and deubiquitinating enzyme activities. The UPS inhibitory potencies of the dirhodium(II,II) carboxylates also exhibit strong correlation with the cytotoxicities. Of note, the dirhodium(II,II) carboxylates inhibit UPS at concentrations that were at least 10-fold lower than that required for eliciting DNA damage as determined by comet assay. While cisplatin, oxaliplatin and carboplatin readily induce significant double strand break as indicated by γ-H2AX induction, the dirhodium(II,II) carboxylates do not. Our findings revealed that the dirhodium(II,II) carboxylates exhibit potent UPS inhibitory property which is linked to their cytotoxic actions.

Diastereoselective ruthenium porphyrin-catalyzed tandem nitrone formation/1,3-dipolar cycloaddition for isoxazolidines. Synthesis, in silico docking study and in vitro biological activities

Ruthenium porphyrin catalyzes tandem nitrone formation/1,3-dipolar cycloaddition of diazo compounds, nitrosoarenes and alkenes to form isoxazolidines in good to high yields and with excellent regio-, chemo- and diastereo-selectivities. A broad substrate scope of alkenes is applicable to this protocol and various functional groups are compatible with the reaction conditions. In silico analysis and in vitro biological experiments revealed that some of the new isoxazolidines synthesized in this work could act as leukotriene A4 hydrolase inhibitors.

An ytterbium(III) porphyrin induces endoplasmic reticulum stress and apoptosis in cancer cells: cytotoxicity and transcriptomics studies

In the literature, very few ytterbium(III) complexes have been reported to display promising anti-cancer activities without photoactivation or conjugation to cytotoxic counterparts/radionuclides. By employing porphyrinato ligands, which provide a rigid molecular scaffold for the ytterbium(III) ion and enhance cellular-uptake efficacy, we have prepared and structurally characterized a series of ytterbium(III) porphyrin complexes showing potent anti-cancer activities with cytotoxic IC50 values down to the sub-micromolar range. The notable example is an ytterbium(III) octaethylporphyrin complex (1) which exists as a dimeric hydroxyl-bridged complex [Yb2(OEP)2(μ-OH)2] (where H2OEP = octaethylporphyrin) in CH2Cl2 solution and in solid state, and as monomeric [Yb(OEP)(DMSO)(OH)(OH2)] in DMSO/aqueous solution. Unlike various anti-cancer lanthanide complexes which are proposed to target cellular DNA, transcriptomics data, bioinformatics connectivity map analysis and biochemical experiments altogether indicate that 1 exerts its anti-cancer effect through apoptosis that is highly associated with the endoplasmic reticulum stress pathway.

Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study

Topoisomerase IB (Top1) inhibitors, such as camptothecin (CPT), stabilize the Top1-DNA cleavage complex in a DNA sequence-dependent manner. The sequence selectivity of Top1 inhibitors is important for targeting specific genomic sequences of therapeutic value. However, the molecular mechanisms underlying this selectivity remain largely unknown. We performed molecular dynamics simulations to delineate structural, dynamic and energetic features that contribute to the differential sequence selectivity of the Top1 inhibitors. We found the sequence selectivity of CPT to be highly correlated with the drug binding energies, dynamic and structural properties of the linker domain. Chemical insights, gained by per-residue binding energy analysis revealed that the non-polar interaction between CPT and nucleotide at the +1 position of the cleavage site was the major (favorable) contributor to the total binding energy. Mechanistic insights gained by a potential of mean force analysis implicated that the drug dissociation step was associated with the sequence selectivity. Pharmaceutical insights gained by our molecular dynamics analyses explained why LMP-776, an indenoisoquinoline derivative under clinical development at the National Institutes of Health, displays different sequence selectivity when compared with camptothecin and its clinical derivatives.