Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as one of the most promising targeted drug for new cancer therapeutics, is limited in clinical application by the evolution of resistance in many cancer cell lines, especially in malignant melanoma. Thus, it is urgently needed to identify chemosensitizers to enhance the apoptotic inducing efficacy of TRAIL and overcome resistance of malignant melanoma cells. Herein, we reported that 3,3'-diselenodipropionic acid (DSeA), a Selenocysteine derivative, could synergistically enhance the growth inhibitory effect of TRAIL on A375 melanoma cells though induction of ROS-dependent apoptosis with involvement of PTEN-mediated Akt inactivation and DNA damage-mediated p53 phosphorylation, which subsequently activated mitochondrial and death receptor apoptotic pathways. Moreover, silencing of p53 down-regulated the expression levels of p53-inducible genes, and effectively blocked the cell apoptosis. Suppression of PI3K significantly increased the apoptotic cell death. In contrast, antioxidants effectively reversed the cell apoptosis through regulation of Akt and p53 signaling pathways. Taken together, the combination of DSeA and TRAIL could be a novel strategy to overcome TRAIL resistance in malignant melanoma, and DSeA may be candidates for further evaluation as a chemosensitizer in clinical trails.
Highlights
The increased incidence of malignant melanoma in the last decades, its high mortality and pronounced therapy resistance pose an enormous challenge [1]
It is of great importance to search for agents that could enhance the sensitivity of cancer cells to Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)
We showed for the first time that diselenodipropionic acid (DSeA), as a potential chemosensitizer, synergistically enhanced the apoptotic inducing efficacy of TRAIL in A375 cells but not in normal cells
Summary
The increased incidence of malignant melanoma in the last decades, its high mortality and pronounced therapy resistance pose an enormous challenge [1]. Most advanced melanomas respond poorly to radiotherapy and chemotherapy and no effective therapy exists to inhibit the metastatic spread of this cancer [2]. Most cancer therapies involve multiple agents, as it is almost universally the case that single drugs or single-target drugs is no longer appropriate for treatment of melanoma, owing to increasing dosage in the clinic has resulted in high toxicity, drug resistance, and unavoidable side effects [3]. It is badly needed to identify chemosensitizers to enhance the apoptotic inducing efficacy of clinical chemotherapeutic drugs and overcome multi-drug resistance (MDR) to kill malignant melanoma cells
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