Small Molecule Therapeutics SmacMimetics in Combinationwith TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stemcells (CSC) have been shownwith resistanceagainst therapies and thus consideredas the initiator of recurrenceandmetastasis in tumors,where the antiapoptotic propertyofCSCsplay an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis.Here, the effects of Smacmimetics on theCSCsof nasopharyngeal carcinomawere studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 asmodels.We found that one of the clones, S18, hadCSC-like properties and IAPswere overexpressed. The combination of Smacmimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colonyand sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stemcells, and this combination treatment shouldbe considered as a promising strategy for the treatment of nasopharyngeal carcinoma. Mol Cancer Ther; 12(9); 1728–37. 2013 AACR.