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

Lum, Ching Tung; Yang, Zhen; Li, Hoi Yee; Sun, Rong; Fan, Sheung Tat; Poon, Ronnie Tung Ping; Lin, Marie C.M.; Ming, Chi; Kung, Hsiang Fu

doi:10.1002/ijc.21484

Cited by 76 publications

(40 citation statements)

References 37 publications

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“…It displayed antiproliferative activity in several types of human cancer cells (Wang et al, 2005(Wang et al, , 2006Lum et al, 2006). However, the precise target and mechanism of action of gold(III) porphyrin 1a on tumour cells remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Akt sensitises neuroblastoma cells to gold(III) porphyrin 1a, a novel antitumour drug induced apoptosis and growth inhibition

Xie

Sun

et al. 2009

Br J Cancer

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BACKGROUND: Gold(III) porphyrin 1a is a new class of anticancer drug, which inhibits cell proliferation of wide range of human cancer cell lines and induces apoptosis in human nasopharyngeal carcinoma cells. However, the underlying signalling mechanism by which gold(III) porphyrin 1a modifies the intracellular apoptosis pathways in tumour cells has not been explained in detail in neuroblastoma cells. METHODS: Cell proliferation and apoptosis were determined by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Annexin V binding, respectively. Western blot assay was used to detect proteins involved in apoptotic and Akt pathways. In vivo tumour growth was assessed by inoculating tumour cells to nude mice subcutaneously, and gold(III) porphyrin 1a was administrated intravenously. RESULTS: This study assessed the antitumour effect and mechanism of gold(III) porphyrin 1a on neuroblastoma in vitro and in vivo. Gold(III) porphyrin 1a displayed a growth inhibition and induction of apoptosis in neuroblastoma cells effectively in vitro, which was accompanied with release of cytochrome c and Smac/DIABLO and caspases activation. Further studies indicated that gold(III) porphyrin 1a inhibited X-linked inhibitor of apoptosis (XIAP). However, we found that gold(III) porphyrin 1a can induce a survival signal, Akt activation within minutes and could last for at least 24 h. To further confirm association between activation of Akt and the effectiveness of gold(III) porphyrin 1a, neuroblastoma cells were treated with API-2, an Akt-specific inhibitor. API-2 sensitised cells to gold(III) porphyrin 1a-induced apoptosis and growth inhibition. CONCLUSION: These results suggested that Akt may be considered as a molecular 'brake' that neuroblastoma cells rely on to slow down gold(III) porphyrin 1a-induced apoptosis and antiproliferation. Gold(III) porphyrin 1a is a mitochondrial apoptotic stimulus but also activates Akt, suggesting an involvement of Akt in mediating the effectiveness to growth inhibition and apoptosis by gold(III) porphyrin 1a and that inhibition of Akt can enhance the anticancer activity of gold(III) porphyrin 1a in neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Akt sensitises neuroblastoma cells to gold(III) porphyrin 1a, a novel antitumour drug induced apoptosis and growth inhibition

Xie

Sun

et al. 2009

Br J Cancer

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“…Normal and tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. The paraffin-embedded tissues were cut into 5-Am thick sections and subjected to H&E and immunohistochemical staining, as previously described (27).…”

Section: Methodsmentioning

confidence: 99%

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

Shen¹,

Yang

Gao³

et al. 2008

Cancer Research

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The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0 -G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and B fibroblast growth factor (bFGF)/B fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2 -kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. [Cancer Res 2008;68(2):404-14]

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“…Efficacy and toxicity data are now available for the gold(III) porphyrins developed by Che and co-workers 125 and for the gold(III) dithiocarbamates developed by Fregona and coworkers. 88 The efficacy of gold(III) porphyrin 1a has been evaluated in an orthotopic rat hepatocellular carcinoma model.…”

Section: B Efficacy Data In In Vivo Studiesmentioning

confidence: 98%

Gold compounds as anticancer agents: chemistry, cellular pharmacology, and preclinical studies

et al. 2009

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Gold compounds are a class of metallodrugs with great potential for cancer treatment. During the last two decades, a large variety of gold(I) and gold(III) compounds are reported to possess relevant antiproliferative properties in vitro against selected human tumor cell lines, qualifying themselves as excellent candidates for further pharmacological evaluation. The unique chemical properties of the gold center confer very interesting and innovative pharmacological profiles to gold-based metallodrugs. The primary goal of this review is to define the state of the art of preclinical studies on anticancer gold compounds, carried out either in vitro or in vivo. The available investigations of anticancer gold compounds are analyzed in detail, and particular attention is devoted to underlying molecular mechanisms. Notably, a few biophysical studies reveal that the interactions of cytotoxic gold compounds with DNA are generally far weaker than those of platinum drugs, implying the occurrence of a substantially different mode of action. A variety of alternative mechanisms were thus proposed, of which those involving either direct mitochondrial damage or proteasome inhibition or modulation of specific kinases are now highly credited. The overall perspectives on the development of gold compounds as effective anticancer drugs with an innovative mechanism of action are critically discussed on the basis of the available experimental evidence.

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

Cited by 76 publications

References 37 publications

Inhibition of Akt sensitises neuroblastoma cells to gold(III) porphyrin 1a, a novel antitumour drug induced apoptosis and growth inhibition

Inhibition of Akt sensitises neuroblastoma cells to gold(III) porphyrin 1a, a novel antitumour drug induced apoptosis and growth inhibition

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

Gold compounds as anticancer agents: chemistry, cellular pharmacology, and preclinical studies

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