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Updated: Jan 25, 2026
Author Spotlight: High-Throughput Screening to Obtain Crystal Hits for Protein Crystallography
Published on: March 10, 2023
A cell-based high-throughput screen to identify synergistic TRAIL sensitizers
Nancy Lynn Booth1, Thomas J Sayers, Alan D Brooks
1Molecular Targets Development Program, Center for Cancer Research, NCI-Frederick, Frederick, MD 21702, USA. nancylynnbooth@gmail.com
Abstract:
We have developed a high-throughput screen (HTS) to search for novel molecules that can synergize with TRAIL, thus promoting apoptosis of ACHN renal tumor cells in a combinatorial fashion. The HTS detects synthetic compounds and pure natural products that can pre-sensitize the cancer cells to TRAIL-mediated apoptosis, yet have limited toxicity on their own. We have taken into account the individual effects of the single agents, versus the combination, and have identified hits that are synergistic, synergistic-toxic, or additive when combined with TRAIL in promoting tumor cell death. Preliminary mechanistic studies indicate that a subset of the synergistic TRAIL sensitizers act very rapidly to promote cleavage and activation of caspase-8 following TRAIL binding. Caspase-8 is an apical enzyme that initiates programmed cell death via the extrinsic apoptotic pathway. Thus, these TRAIL sensitizers may potentially reduce resistance of tumor cells to TRAIL-mediated apoptosis. Two representative sensitizers were found to increase levels of p53 but did not inhibit the proteasome, suggesting that early DNA damage-sensing pathways may be involved in their mechanisms of action.
Insights
Researchers identified new molecules that enhance TRAIL therapy for renal tumors. These compounds sensitize cancer cells to TRAIL-induced apoptosis, offering a promising combination strategy for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor cells often develop resistance to apoptosis-inducing agents like TRAIL.
- Novel therapeutic strategies are needed to overcome this resistance and enhance treatment efficacy.
Purpose of the Study:
- To develop a high-throughput screen (HTS) to identify molecules that synergize with TRAIL for renal tumor cell apoptosis.
- To find compounds that pre-sensitize cancer cells to TRAIL-mediated apoptosis with limited intrinsic toxicity.
Main Methods:
- Utilized a high-throughput screen (HTS) to identify synergistic compounds.
- Assessed individual agent toxicity versus combination effects.
- Conducted preliminary mechanistic studies on synergistic TRAIL sensitizers.
Main Results:
- Identified synergistic, synergistic-toxic, and additive compounds when combined with TRAIL.
- Discovered that some sensitizers rapidly activate caspase-8 following TRAIL binding.
- Observed increased p53 levels in cells treated with representative sensitizers, without proteasome inhibition.
Conclusions:
- Novel TRAIL sensitizers were identified, potentially overcoming resistance to TRAIL-mediated apoptosis.
- Mechanistic insights suggest caspase-8 activation and possibly DNA damage-sensing pathways are involved.
- These findings offer a promising combinatorial approach for treating renal tumors.
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