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Using natural products to promote caspase-8-dependent cancer cell death

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.

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Abbreviations

APCs:

Antigen-presenting cells

Bak:

Bcl-2 homologous antagonist killer

Bax:

Bcl-2-associated X protein

Bid:

BH3-interacting domain death agonist

c-FLIP:

Cellular FLICE inhibitory protein

DAMPs:

Danger-associated molecular patterns

DD:

Death domain

DED:

Death effector domains

DISC:

Death-inducing signaling complex

DRs:

Death receptors

dsRNA:

Double-stranded RNA

FADD:

Fas-associated protein with death domain

Fas L:

Fas ligand

IAP:

Inhibitor of apoptosis,

MAPK:

Mitogen-activated protein kinase

MLKL:

Mixed lineage kinase domain-like

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRs:

NOD-like receptors

OPG:

Osteoprotegerin

PCD:

Programmed cell death

PI3K/AKT:

Phosphoinositide 3-kinase/protein kinase B

poly(I:C):

Polyinosinic–polycytidylic acid

PRR:

Pattern recognition receptor

RHIM RIP:

Homotypic interaction motif

RIG1:

Retinoic acid-inducible gene I like receptors

RIP1:

Receptor-interacting protein 1

SAR:

Structure–activity relationship

Smac:

Second mitochondria-derived activator of caspase

TIR:

Toll/interleukin-1 receptor

TLRs:

Toll-like receptors

TNF:

Tumor necrosis factor

TNFR :

Tumor necrosis factor receptor

TRADD:

TNFR-associated death domain

TRAF2:

Tumor necrosis factor receptor-associated protein

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

TRIF:

TIR-domain-containing adapter-inducing interferon-β

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Acknowledgments

We thank Andrew Sayers for his assistance with the artwork. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. 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 US Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the University of Arizona College of Agriculture and Life Sciences.

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Authors and Affiliations

  1. Cancer and Inflammation Program, National Cancer Institute, Frederick, Frederick, MD, 21702, USA

    Poonam Tewary & Thomas J. Sayers

  2. Basic Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA

    Poonam Tewary & Thomas J. Sayers

  3. Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ, USA

    A. A. Leslie Gunatilaka

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  1. Poonam Tewary
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  2. A. A. Leslie Gunatilaka
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  3. Thomas J. Sayers
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Correspondence to Poonam Tewary or Thomas J. Sayers.

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Conflict of interest

Thomas Sayers is an inventor on US patent (No. 9,238,069) Method of Sensitizing Cancer Cells to the Cytotoxic Effects of Death Receptor Ligands for Cancer Treatment assigned to the US Government. Thomas Sayers, A. A. Leslie Gunatilaka and Poonam Tewary have filed a patent application based on ability of active 17-beta hydroxy withanolides to promote death in cancer cells in response to TNF family death ligands and TLR3 ligands such as poly(I:C).

Additional information

This paper is a Focussed Research Review based on a presentation given at the Fifteenth International Conference on Progress in Vaccination against Cancer (PIVAC 15), held in Tübingen, Germany, 6th–8th October, 2015. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews and meeting report.

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Tewary, P., Gunatilaka, A.A.L. & Sayers, T.J. Using natural products to promote caspase-8-dependent cancer cell death. Cancer Immunol Immunother 66, 223–231 (2017). https://doi.org/10.1007/s00262-016-1855-0

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