Suberoylanilide hydroxamic acid sensitizes human oral cancer cells to TRAIL-induced apoptosis through increase DR5 expression

Abstract

Suberoylanilide hydroxamic acid has been shown to selectively induce tumor apoptosis in cell cultures and animal models in several types of cancers and is about as a promising new class of chemotherapeutic agents. In addition, suberoylanilide hydroxamic acid showed synergistic anticancer activity with radiation, cisplatin, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in some cancers. Here, we report suberoylanilide hydroxamic acid also induced apoptosis in human oral cancer cells. Western blotting showed suberoylanilide hydroxamic acid increased Fas, Fas ligand, DR4, and DR5 protein expression and activated caspase-8 and caspase-9. The apoptosis was almost completely inhibited by caspase-8 inhibitor Z-IETD-FMK and attenuated by caspase-9 inhibitor Z-LEHD-FMK. Human recombinant DR5/Fc chimera protein but not Fas/Fc or DR4/Fc significantly inhibited apoptosis induced by suberoylanilide hydroxamic acid. These results suggest that suberoylanilide hydroxamic acid induces apoptosis mainly through activation of DR5/ TRAIL death pathway. Furthermore, subtoxic concentrations of suberoylanilide hydroxamic acid sensitize two TRAIL resistant human oral cancer cells, SAS and Ca9-22, to exogenous recombinant TRAIL-induced apoptosis in a p53-independent manner. Combined treatment of suberoylanilide hydroxamic acid and TRAIL may be used as a new promising therapy for oral cancer. [Mol Cancer Ther 2009;8(9):2718-25]

Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells

“…Some conventional chemotherapeutic drugs, such as etoposide and doxorubicin, can induce apoptosis via DR5 upregulation in a p53-dependent manner. However, DR5 can also be regulated in a cell type-specific, trigger-dependent, and p53-independent manner, but the underlying mechanisms remain largely unclear [53,54]. Our data showed p53 was not associated with DR5 upregulation in ChK-treated OVCAR-3 and A2780/CP70 cells, which was in agreement with the previous study conducted in human ovarian cancer SKOV3 cells induced by CHM-1 [55].…”

The negative prognostic value of TRAIL overexpression in oral squamous cell carcinomas does not preclude the potential therapeutic use of recombinant TRAIL

“…Interestingly, however, we also found that recombinant soluble TRAIL showed high cytotoxicity when added to OSCC cell lines. In line with our current results, it has been previously reported that treatment with TRAIL, used either alone or in combination with other drugs, resulted in induction of cell death in head and neck squamous cell carcinomas [24][25][26][27]. Taken together, our data clearly indicate that a high expression of TRAIL in OSCC cells, as observed both at immunohistochemistry and at flow cytometry, does not necessarily imply that OSCC cells are resistant to cytotoxicity induced by recombinant soluble TRAIL.…”

Generation of Reactive Oxygen Species by Polyenylpyrroles Derivatives Causes DNA Damage Leading to G2/M Arrest and Apoptosis in Human Oral Squamous Cell Carcinoma Cells

“…The viability of OEC-M1 cells, SCC-4 cells, and HSC-3 cells were all reduced by compound 1a ; however, the killing effect of compound 1a on these cell lines might not be mediated by p53. In contrast to OEC-M1 cells, SAS cells have a high level expression of EGFR [26], and is resistant to TRAIL-induced apoptosis [27]. In this study, SAS cells were shown to be resistant to compound 1a treatment and we have yet to find the cause for this resistance.…”