Ching Tung Lum

Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma

Recently, a series of gold(III) meso‐tetraarylporphyrins that are stable against demetallation in physiological conditions have been synthesized. In the present study, the antitumor effects of one of these compounds, gold(III) meso‐tetraarylporphyrin 1a (gold‐1a) was investigated in an orthotopic rat hepatocellular carcinoma (HCC) model as well as using a HCC cell line. The rat HCC model was induced by injection of rat hepatoma cells, McA‐RH7777, into the left lobe of the liver. Seven days after tumor cell inoculation, gold‐1a was injected directly into the tumor nodule at different doses, followed by the same doses via intraperitoneal injection twice a week. Gold‐1a administration significantly prolonged the survival of HCC‐bearing rats. Importantly, gold‐1a induced necrosis as well as apoptosis in the tumor tissues, but not in the normal liver tissues. Furthermore, gold‐1a treatment neither caused significant drop in body weight of the rats nor affected plasma aspartate aminotransferase level. In the in vitro studies, we observed that gold‐1a treatment inhibited the proliferation of McA‐RH7777 cells. Gold‐1a upregulated genes that increase apoptosis, stabilize p53, decrease proliferation and downregulated genes playing roles in angiogenesis, invasion, and metabolism, as demonstrated by microarray. In particular, the compound upregulated 2 members of the growth arrest and DNA damage (Gadd) inducible gene family, Gadd34 and Gadd153. Suppression of Gadd34 and Gadd153 in McA‐RH7777 cells by small hairpin RNA reduced the gold‐1a‐induced apoptosis and growth inhibition, indicating that gold‐1a mediated its effects via upregulation of Gadd34 and Gadd153. Results from our study demonstrated that gold‐1a might be a novel promising chemocytotoxic agent for treating HCC.

Potent inhibition of SARS-associated coronavirus (SCoV) infection and replication by type I interferons (IFN-α/β) but not by type II interferon (IFN-γ)

We sought to investigate the anti-severe acute respiratory syndrome (SARS)-associated coronavirus (SCoV) activities of type I (alpha and beta) and type II (gamma) interferons (IFN) in vitro. Type I IFNs protected cells from cytopathic effects (CPE) induced by SCoV, and inhibited viral genomic RNA replication in FRhk-4 cells (measured by quantitative RT-PCR) in a dose-dependent manner. Intracellular viral RNA copies were reduced 50% by IFN-alpha at a concentration of 25 U/ml and by IFN-beta at a concentration of 14 U/ml. IFN-gamma had fewer effects on inhibition of viral infection and replication. The type I IFN receptor signaling pathway in host cells is mainly involved in the inhibition of SCoV infection and replication. Type I IFNs could be used as potential agents for anti-SARS treatment.

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

XAF1 (XIAP‐associated factor 1) is a novel XIAP binding protein that can antagonize XIAP and sensitize cells to other cell death triggers. Our previous results have shown that aberrant hypermethylation of the CpG sites in XAF1 promoter is strongly associated with lower expression of XAF1 in gastric cancers. In our study, we investigated the effect of restoration of XAF1 expression on growth of gastric cancers. We found that the restoration of XAF1 expression suppressed anchorage‐dependent and ‐independent growth and increased sensitivity to TRAIL and drug‐induced apoptosis. Stable cell clones expressing XAF1 exhibited delayed tumor initiation in nude mice. Restoration of XAF1 expression mediated by adenovirus vector greatly increased apoptosis in gastric cancer cell lines in a time‐ and dose‐dependent manner and sensitized cancer cells to TRAIL and drugs‐induced apoptosis. Adeno‐XAF1 transduction induced cell cycle G2/M arrest and upregulated the expression of p21 and downregulated the expression of cyclin B1 and cdc2. Notably, adeno‐XAF1 treatment significantly inhibited tumor growth, strongly enhanced the antitumor activity of TRAIL in a gastric cancer xenograft model in vivo, and significantly prolonged the survival time of animals bearing tumor xenografts. Complete eradication of established tumors was achieved on combined treatment with adeno‐XAF1 and TRAIL. Our results document that the restoration of XAF1 inhibits gastric tumorigenesis and tumor growth and that XAF1 is a promising candidate for cancer gene therapy.

Gold(III) porphyrin 1a inhibited nasopharyngeal carcinoma metastasis in vivo and inhibited cell migration and invasion in vitro

A physiologically stable gold compound, gold(III) meso-tetraphenylporphyrin (gold-1a), has been shown to be effective in inducing apoptosis and prolonging the survival of hepatocellular carcinoma (HCC)-bearing rats as well as inhibiting the tumor growth of mice bearing nasopharyngeal carcinoma (NPC), neuroblastoma and colon carcinoma. In this study, we showed that gold-1a prolonged the survival of NPC metastasis-bearing mice and inhibited intrahepatic and lung metastasis. Histologically, gold-1a markedly reduced tumor microvessel formation. Consistently, in in vitro studies, gold-1a inhibited migration and invasion of C666-1 human NPC cells. The data strongly support the use of gold(III) compounds to treat cancer metastasis.

Gold(III) complexes inhibit growth of cisplatin-resistant ovarian cancer in association with upregulation of proapoptotic PMS2 gene.

Various gold complexes have been known to overcome cisplatin resistance in cancer cells. Yet, their in vivo anti-tumor efficacies and detailed action mechanisms in overcoming this resistance remain largely unexplored. In this work we have established a xenograft model simultaneously consisting of both cisplatin-sensitive and cisplatin-resistant tumors by inoculating human ovarian cancer cells A2780 and its cisplatin-resistant variant A2780cis into different flanks of the same nude mouse. Towards this model, a gold(III) porphyrin complex [AuIII(TPP)]Cl (gold-1a, wherein [TPP]2− = meso-tetraphenylporphyrinato ligand) was found to effectively inhibit the growth of both kinds of tumors, while cisplatin failed to suppress the growth of A2780cis tumors under similar conditions. In both A2780 and A2780cis cells, gold-1a was found to transcriptionally upregulate postmeiotic segregation increased 2 (PMS2) which has DNA mismatch repair and proapoptotic functions. Suppression of PMS2 by RNA interference in A2780cis cells partially rescued the gold-1a-induced death of the cells, indicating that gold-1a inhibited growth of cisplatin-resistant ovarian cancer in association with upregulation of this gene. Two other stable gold(III) analogues including gold(III) octaethylporphyrin (2) and gold(III)-NHC (3) complexes also displayed similar anti-cancer activities on A2780cis cells and capability in PMS2 regulation. In contrast, a gold(I) phosphine complex (4), a gold(I) thiourea complex (5), KAuIIICl4 and cisplatin all displayed a preferential cytotoxicity only towards the cisplatin-sensitive A2780 cells. Taken together, this work has demonstrated the prospect of gold(III) complexes for the treatment of cisplatin-resistant/relapsed ovarian cancers.

Gold(III) porphyrin 1a prolongs the survival of melanoma-bearing mice and inhibits angiogenesis

Abstract Background. Gold(III) meso-tetraphenylporphyrin (gold-1a) has previously been shown to prolong the survival of hepatocellular carcinoma (HCC)-bearing rats and nasopharyngeal carcinoma (NPC) metastasis-bearing mice. It has also been proved to inhibit the tumor growth of mice bearing NPC, neuroblastoma and colon carcinoma. Mechanistically, gold-1a induces apoptosis, inhibits cell migration and invasion. In this study the efficacies of gold-1a in inhibiting melanoma and angiogenesis were investigated. Material and methods. A mouse melanoma model was used to investigate the efficacy of gold-1a in inhibiting angiogenesis, tumor growth and prolonging the survival of the tumor-bearing animals. The model was established by inoculation of 2 × 105 B16-F1 mouse melanoma cells into the right back flanks of the mice by subcutaneous inoculation. When the tumors grew to 0.2–0.4 cm in diameters, the mice were treated with gold-1a, solvent control or dacarbazine (DTIC) for comparison. Tumor sizes and animal survivals were monitored throughout the experiment. Tumor tissues were collected and immunohistochemically stained with CD31 antibodies for evaluation of intra-tumoral microvessel density (iMVD). Results and conclusion. Gold-1a significantly prolonged the survivals, reduced angiogenesis and tumor growth rates of melanoma-bearing mice. The compound induced necrosis and apoptosis in the mouse melanoma tissues. Gold-1a also downregulated the expression of genes playing roles in angiogenesis. Gold-1a may potentially be used to treat melanoma in patients.

Alkynyl gold(I) phosphane complexes: Evaluation of structure–activity-relationships for the phosphane ligands, effects on key signaling proteins and preliminary in-vivo studies with a nanoformulated complex

Gold alkynyl complexes with phosphane ligands of the type (alkynyl)Au(I)(phosphane) represent a group of bioorganometallics, which has only recently been evaluated biologically in more detail. Structure-activity-relationship studies regarding the residues of the phosphane ligand (P(Ph)3, P(2-furyl)3, P(DAPTA)3, P(PTA)3, P(Et)3, P(Me)3) of complexes with an 4-ethynylanisole alkyne ligand revealed no strong differences concerning cytotoxicity. However, a relevant preference for the heteroatom free alkyl/aryl residues concerning inhibition of the target enzyme thioredoxin reductase was evident. Complex 1 with the triphenylphosphane ligand was selected for further studies, in which clear effects on cell morphology were monitored by time-lapse microscopy. Effects on cellular signaling were determined by ELISA microarrays and showed a significant induction of the phosphorylation of ERK1 (extracellular signal related kinase 1), ERK2 and HSP27 (heat shock protein 27) in HT-29 cells. Application of 1 in-vivo in a mouse xenograft model was found to be challenging due to the low solubility of the complex and required a formulation strategy based on a peanut oil nanoemulsion.

IFITM1 promotes the metastasis of human colorectal cancer via CAV-1.

Interferon-induced transmembrane protein 1 (IFITM1) is one of the interferon-induced transmembrane protein family members. In this study, we reported that the elevated IFITM1 expression in human colorectal cancer (CRC) significantly correlated with CRC lymph node and distance metastasis as well as a more advanced clinical stage. Importantly, elevated IFITM1 expression is an independent prognostic factor for poor survival. To investigate the molecular mechanisms, we showed that over-expression of IFITM1 in CRC cells promoted, whereas knockdown of IFITM1 expression inhibited, cell migration/invasion and tumorigenicity in vitro. Furthermore, we identified Caveolin-1 (CAV1) as a downstream target of IFITM1-induced cell invasion, as knockdown of CAV1 abrogated siIFITM1 mediated inhibition of cell invasion in CRC cells. In addition, in a CRC cohort of 229 patients, the expression of IFITM1 inversely correlated with the expression of CAV1. These results suggested that IFITM1 promotes the aggressiveness of CRC cells, and it is a potential prognostic marker and therapeutic target for CRC.

Genome-Wide Study of The Anti-Tumor Effect of Gold-1a, a Novel Chemo-Cytotoxic Agent for Hepatocellular Carcinoma (HCC)

Method 8 rats were fed choline supplied (CS) diet, 32 rats were fed choline deficient (CD) diet for 3 weeks to develope NASH, then divided 4 groups randomly. They were lavaged with seal oil (0.5g/kg ·d, 1.6 g/kg ·d, 4.8g/kg ·d) and olive oil (2ml/d) for 8 weeks respectively. Serum biochemistry marker were determined by automatic biochemistry analyzer. RT-PCR was performed to measure gene expression of adiponectin and adipoR2 normalized against the housekeeping genesβ-actin. Result Compared with CS diet group, olive oil treatment group (control group, group2) have markedly liver fat degeneration and inflammatory cell infiltration. Compared with group 2, medium and high dose seal oil (group 4 and 5) induced a significant decrease of serum ALT, AST, ALP; Serum cholesterol (CH) and triglyceride (TG) also decreased, but have no statistically significance. Serum ALT, AST, ALP, CH and TG have no markedly change in low dose seal oil treatment group (group 3). Rats of group 4 and 5 have significantly decreased incidence and extent of necrosis, decreased fibrous degeneration and inflammatory cell infiltration. According to the inflammatory and fibrosis grade, the score of group 4 and 5 decreased significantly, score of group 3 also decreased, without statistically significance. Compared with the control group, increased expression of adiponectin and AdipoR2 were significantly detected in three seal oil group. With the dose of seal oil increased, the expression of adiponectin and AdipoR2 also increased. Significance between the three groups were also exist. Conclusion The hepatoprotection in this animal models suggest seal oil may be useful in the NASH treatment. Seal oil may enhanced the expression of adiponectin and AdipoR2 gene.

Restoration of XAF1 expression inhibits gastric and colonic tumorigenesis in vivo

This journal suppl. contain abstracts of the 8th Medical Research Conference, Medical Science Group, Queen Mary Hospital, Hong Kong