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

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.

The cytotoxic effects of lipidic formulated gold porphyrin nanoparticles for the treatment of neuroblastoma

“…The importance of free gold porphyrin nanoparticles against neuroblastoma has been shown in previous reports of in vitro and preclinical studies. 23 Consistent with previous findings, our data show that the free gold porphyrin nanoparticles are able to kill neuroblastoma cells. Our in vitro cytotoxicity examination demonstrated the effective killing of neuroblastoma cells using the carrier system.…”

Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?

“…Further, work was directed to address the possible mechanisms behind therapeutic resistance encountered in neuroblastoma cells. The activation of protein kinase B (PKB), also known as Akt, by ( 18 ) before the onset of apoptosis was postulated as the key reason behind the induction of the encountered resistance [ 69 ]. This hypothesis was strengthened by the fact that the anti-cancer activity of ( 18 ) in neuroblastomas was enhanced after the introduction of Akt/protein kinase B signalling inhibitor (API-2).…”

Porphyrin/Chlorin Derivatives as Promising Molecules for Therapy of Colorectal Cancer

“…Among the metal-based compounds used for medical applications, porphyrin gold(III) complexes are receiving increasing attention as chemotherapies rather than PDT drugs because of their promising in vitro and in vivo anticancer activities [ 99 , 100 , 101 , 102 ]. It has been shown that porphyrin is one of the best-stabilizing ligands of gold(III) for avoiding its reduction, and porphyrin substitutions increase its complex solubility and cytotoxicity [ 103 , 104 , 105 ].…”