Molecular Diagnostics

British Journal of Cancer (2009) 101, 342–349. doi:10.1038/sj.bjc.6605147 www.bjcancer.com
Published online 23 June 2009

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

W Li1,2, Y Xie1, R W-Y Sun3, Q Liu1, J Young1, W-Y Yu3, C-M Che3, P K Tam1 and Y Ren1,4

  1. 1Department of Surgery, University of Hong Kong, Pokfulam Road, Hong Kong, PR China
  2. 2Laboratory in Department of Surgery, The First Affiliated Hospital, Guangzhou Medical College, Guangzhou, Guangdong, PR China
  3. 3Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong, PR China
  4. 4Department of Cell Biology and Neuroscience, Rutgers University, NJ 08854, USA

Correspondence: Dr Y Ren, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, D-251, Piscataway, NJ 08854, USA. E-mail: ren@dls.rutgers.edu; Professor C-M Che, Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Pokfulam Road, Hong Kong, PR China. E-mail: cmche@hku.hk; Professor PK Tam, Department of Surgery, University of Hong Kong, Pokfulam Road, Hong Kong, PR China. E-mail: paultam@hkucc.hku.hk

Received 22 December 2008; Revised 7 May 2009; Accepted 28 May 2009; Published online 23 June 2009.

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Abstract

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.

Keywords:

Akt, apoptosis, caspases, gold(III) porphyrin 1a, neuroblastoma