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A cell-based high-throughput screen to identify synergistic TRAIL sensitizers

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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.

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Abbreviations

TRAIL:

Tumor necrosis factor-α-related apoptosis-inducing ligand

HTS:

High-throughput screen

TNFα:

Tumor necrosis factor-alpha

TR1/TR2/TR3/TR4:

TRAIL death receptors-1/-2/-3/-4

XTT:

2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide

SRB:

Sulforhodamine B

TCA:

Trichloroacetic acid

DMSO:

Dimethylsulfoxide

FBS:

Fetal bovine serum

−TRAIL:

In the absence of TRAIL ligand

+TRAIL:

In the presence of TRAIL ligand

%GI:

Percent growth inhibition

MMP:

Mitochondrial membrane potential

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Acknowledgments

Jennifer Wilson generously assisted with numerous XTT assays during the development of the TRAIL HTS; Heidi R. Bokesch conducted LC-MS and NMR quality control evaluations on compounds provided by the NCI Natural Products Repository; and Antony M. Wamiru and Nancy B. Shulley were instrumental in the design and trouble-shooting of Beckman 384-FX robot programs for use in the screen. The authors thank Kirk R. Gustafson for his time to read and comment on the manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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  1. Nancy Lynn Booth

    Present address: Spherix Incorporated, 6430 Rockledge Drive #503, Bethesda, MD, 20817, USA

Authors and Affiliations

  1. Molecular Targets Development Program, Center for Cancer Research, NCI-Frederick, P.O. Box B, Building 1052, Room 121, Frederick, MD, 21702, USA

    Nancy Lynn Booth, Cheryl L. Thomas, Ekaterina I. Goncharova, James B. McMahon & Curtis J. Henrich

  2. Laboratory for Experimental Immunology and Cancer Inflammation Program, Center for Cancer Research, NCI-Frederick, P.O. Box B, Building 560, Room 31-30, Frederick, MD, 21702, USA

    Thomas J. Sayers, Alan D. Brooks & Kristen Jacobsen

  3. SAIC-Frederick, Inc., Frederick, MD, 21702, USA

    Thomas J. Sayers, Alan D. Brooks & Curtis J. Henrich

  4. Data Management Services, Inc., P.O. Box 333, Frederick, MD, 21705, USA

    Ekaterina I. Goncharova

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  1. Nancy Lynn Booth
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Booth, N.L., Sayers, T.J., Brooks, A.D. et al. A cell-based high-throughput screen to identify synergistic TRAIL sensitizers. Cancer Immunol Immunother 58, 1229–1244 (2009). https://doi.org/10.1007/s00262-008-0637-8

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