Radiosensitization of Head and Neck Squamous Cell Carcinoma by a SMAC-Mimetic Compound, SM-164, Requires Activation of Caspases

Abstract

Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small second mitochondria-derived activator of caspase -mimetic compound that promotes degradation of cellular inhibitor of apoptosis-1(cIAP-1; also known as baculoviral IAP repeat-containing protein 2, BIRC2) and releases active caspases from the X-linked inhibitor of apoptosis inhibitory binding as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via short interfering RNA knockdown or a pan-caspase inhibitor, z-VAD-fmk, largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of Bcl-2 that blocks caspase activation and apoptosis induction became sensitive to radiation on Bcl-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NF-kB activation and TNFa secretion, followed by activation of caspase-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients. Mol Cancer Ther; 10(4); 658-69. Ó2011 AACR.

The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma

“…A pronounced increase in karyopyknosis and in Annexin V positive cells was found, while DSB repair was not affected. In the radiosensitive FaDu cell line activation of caspases-3 and -8 was observed, which is consistent with previous reports on other SMAC-mimetics showing radio-sensitization through activation of caspases and enhanced induction of apoptosis [11,12]. However, the radiation-resistant SQ20B exhibited caspase-3 activation, but was exempt of caspase-8 activation at the time points studied.…”

“…Debio 1143 enhanced the in vitro antitumor activity of radiation in the majority of the HNSCC cell lines tested (5/6). These findings corroborate the well described radio-sensitizing effect of several SMAC-mimetics in models including breast cancer [11], HNSCC [12], malignant glioma [13] and colorectal cancer [14] including the recently published radiosensitizing effect of Debio 1143 [15]. In one cell line (SCC15), Debio 1143 combined with RT was poorly effective and the underlying cause should be investigated in more detail as it could provide the basis for a personalized selection of responders in clinical trials.…”

SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death GenesFADDandBIRC2

“…Recently, combinatorial activity of different SMAC mimetics with radiation and induction of TNFα has been demonstrated in lung cancer and HNSCC cell lines (37,38). Partial response in UM-SCC-1 xenografts in the latter study was observed, similar to our results.…”

Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways

“…The radiosensitizing potential of SMAC mimetics was also described by Yang et al, who used Smac-164 in vivo in combination with radiation and showed a significant response in an HNSCC xenograft model. (60) They further demonstrated that in vitro SMAC mimetic radiosensitization in sensitive cells was associated with TNFα secretion.…”