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A novel, soluble compound, C25, sensitizes to TRAIL-induced apoptosis through upregulation of DR5 expression
Michael A James1, William L Seibel, Elena Kupert
1Departments of aSurgery bMedicine, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin cDrug Discovery Center, University of Cincinnati, Cincinnati, Ohio, USA.
Abstract:
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential therapeutic agent that induces apoptosis selectively in tumor cells. However, numerous solid tumor types are resistant to TRAIL. Sensitization to TRAIL has been an area of great research interest, but has met significant challenges because of poor bioavailability, half-life, and solubility of sensitizing compounds such as curcumin. Soluble, TRAIL-sensitizing compounds were screened on the basis of similarity to the redox-active substructure of curcumin and sensitization to TRAIL-induced apoptosis. We determined the effect of the lead compound, C25, in combination with TRAIL in human cancer cell lines using MTS proliferation assays, apoptosis assays, and western blotting. Short hairpin RNA knockdown of death receptor 5 (DR5) was performed to determine whether DR5 upregulation was required for TRAIL-mediated apoptosis. In-vivo efficacy was determined using human lung tumor xenograft models. C25 helped overcome TRAIL resistance by upregulating the expression of the TRAIL receptor DR5 and apoptosis in several tumor cell lines. Blockade of DR5 expression abrogated C25 sensitization to TRAIL, demonstrating the requirement for DR5 upregulation for C25-mediated potentiation of TRAIL-mediated apoptosis. The combination of C25 and TRAIL effectively inhibited tumorigenesis in vivo. This study demonstrates the synergistic efficacy of C25 in sensitization to TRAIL-induced apoptosis in multiple tumor cell types, including highly resistant lung and ovarian tumor cell lines. Furthermore, C25 was efficacious against tumor growth in vivo. Thus, C25 may be a potential therapeutic for cancer in combination with TRAIL or DR5 agonist therapy.
Insights
A novel compound, C25, effectively sensitizes resistant cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy by upregulating the death receptor 5 (DR5). This combination therapy shows significant promise for inhibiting tumor growth in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells, but solid tumors often exhibit resistance.
- Existing TRAIL sensitizers, like curcumin, face challenges with bioavailability, half-life, and solubility.
- Developing effective TRAIL sensitizers is crucial for enhancing cancer therapy.
Purpose of the Study:
- To identify and evaluate novel, soluble compounds that can sensitize TRAIL-resistant cancer cells.
- To investigate the mechanism by which the lead compound, C25, enhances TRAIL-induced apoptosis.
- To assess the in vivo efficacy of C25 in combination with TRAIL for cancer treatment.
Main Methods:
- Screening of soluble compounds based on curcumin's redox-active substructure for TRAIL sensitization.
- In vitro assays including MTS proliferation, apoptosis assays, and Western blotting using human cancer cell lines.
- Short hairpin RNA (shRNA) knockdown of death receptor 5 (DR5) to elucidate its role in C25-mediated sensitization.
- In vivo efficacy studies using human lung tumor xenograft models.
Main Results:
- The lead compound C25 effectively sensitized multiple human cancer cell lines to TRAIL-induced apoptosis.
- C25 upregulated the expression of the TRAIL receptor DR5, which was essential for its sensitizing effect.
- DR5 blockade abrogated C25's ability to potentiate TRAIL-mediated apoptosis.
- Combination therapy with C25 and TRAIL significantly inhibited tumor growth in human lung tumor xenograft models.
Conclusions:
- C25 overcomes TRAIL resistance by upregulating DR5 expression and enhancing TRAIL-induced apoptosis in various tumor types.
- DR5 upregulation is a critical mechanism for C25's potentiation of TRAIL therapy.
- The combination of C25 and TRAIL demonstrates synergistic efficacy and significant in vivo antitumor activity.
- C25 represents a promising therapeutic candidate for combination cancer treatment with TRAIL or DR5 agonists.
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