Motexafin gadolinium (MGd, Xcytrin®) is a tumor-selective expanded porphyrin that targets oxidative stress related proteins. MGd treatment of the follicular lymphoma-derived cell line HF-1 resulted in growth suppression and apoptosis, whereas MGd treatment of the Burkitt’s lymphoma-derived cell line Ramos resulted in growth suppression but not apoptosis. Since phosphorylation status of Akt/PKB kinase is regulated by oxidative stress, we monitored total and phosphorylated Akt (pAkt) in MGd treated HF-1 and Ramos cells. In HF-1, pAkt levels increased within 30 min after MGd treatment but 4 hrs later began to show a progressive decline to approximately 20% of normal levels. The decrease in pAkt occurred prior to cells undergoing apoptosis and was accompanied by an increase in total Akt levels. In Ramos cells, pAkt increased within 30 min after MGd treatment and remained persistently elevated. Since pAkt activates survival pathways, we determined if MGd cytotoxic activity could be enhanced by inhibiting phosphorylation of Akt. The addition of specific inhibitors of Akt phosphorylation (SH-5 or Akt inhibitor 1) reduced pAkt levels in MGd treated HF-1 and Ramos cells and synergistically enhanced MGd-induced cell death. MGd was also evaluated in combination with docetaxel, an inhibitor of microtubule depolymerization. MGd combined with docetaxel resulted in a decrease of pAkt levels and in synergistic cytotoxicity compared to either agent alone. These data point to a potential protective role for pAkt in MGd-treated cells and suggest that MGd activity may be enhanced by combining it with agents that inhibit the phosphorylation of Akt.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]