Abstract
Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells. Rocaglamide alone induced cell cycle arrest, but not apoptosis. Rocaglates averaged 4–5-fold higher potency as TRAIL sensitizers than as protein synthesis inhibitors suggesting a potential window for maximizing TRAIL sensitization while minimizing effects of general protein synthesis inhibition. A wide range of other rocaglate effects (e.g. on JNK or RAF-MEK-ERK signaling, death receptor levels, ROS, ER stress, eIF4E phosphorylation) were assessed, but did not contribute to TRAIL sensitization. Other than a rapid loss of MCL-1, rocaglates had minimal effects on mitochondrial apoptotic pathway proteins. The identification of structurally diverse/mechanistically similar TRAIL sensitizing rocaglates provides insights into both rocaglate structure and function and potential further development for use in RCC-directed combination therapy.
Highlights
Induction of cancer cell-specific apoptosis via activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling has been an attractive goal for cancer therapeutics
Advances in synthesis have led to production of both natural rocaglates and novel rocaglamide analogs, few, if any, of these compounds have been investigated for activity as TRAIL sensitizers and neither ROC nor its analogs have been widely assessed in the context of renal cell carcinoma (RCC) cells
Protein synthesis inhibition by rocaglates resulted in rapid loss of cFLIP protein leading to enhanced death receptor signaling and subsequent caspase-dependent apoptotic cell death upon addition of TRAIL
Summary
Induction of cancer cell-specific apoptosis via activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling has been an attractive goal for cancer therapeutics. Several other cancer-related cellular effects including altered cell cycle progression, RAF-MEK-ERK and p38/JNK signaling, death receptor upregulation, ER stress, generation of reactive oxygen species (ROS), and activation of the intrinsic (mitochondrial) apoptotic pathway have been reported for ROC in various cancer cell types Many of these cellular effects reported for ROC and analogs have been demonstrated to sensitize cells to TRAIL-induced apoptosis[1,2,3,4,5,6]. In order to further investigate the activities and potential for development of rocaglates as TRAIL sensitizers, ROC and 55 natural and synthetic analogs were assessed for their ability to sensitize the well-characterized TRAIL-resistant ACHN RCC cell line to TRAIL-induced apoptosis in parallel with analysis of their protein synthesis inhibitory activity in the same cells under the same conditions. Other previously reported rocaglate effects that are relevant to TRAIL signaling and apoptosis induction were assessed
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