Trichothecenes: immunomodulatory effects, mechanisms, and anti-cancer potential

Abstract

Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an “immune evasion” milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-κB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer.

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Abbreviations

ARNT:

Aryl hydrocarbon receptor nuclear translocator

CaSR:

Calcium-sensing receptor

CDC:

Complement-dependent cytotoxicity

CHOP:

Enhancer-binding protein homologous protein

CREB:

cAMP-response clement-binding protein

DAS:

Diacetoxyscirpenol

DMBA:

7,12-Dimethylbenz[a]anthracene

DON:

Deoxynivalenol

FB1:

Fumonisin B1

FX:

Fusarenon X

GFP:

Green fluorescence protein

GSH:

Glutathione

Hck:

Hemopoietic cell kinase

HIF-1:

Hypoxia-inducible factor 1

mAb:

Monoclonal antibodies

MIP-2:

Macrophage inhibitory protein 2

MyD88:

Myeloid differentiation factor 88

NIV:

Nivalenol

PCD:

Programmed cell death

PCV2:

Porcine circovirus type 2

PCVAD:

Porcine circovirus-associated disease

PI:

Post-injection

PKR:

RNA-activated protein kinase R

PMNs:

Pig polymorphonuclear cells

PP:

Peyer’s patch

PRRS:

Porcine reproductive and respiratory syndrome

PRRSV:

Porcine reproductive and respiratory syndrome virus

PTPC:

Permeability transition pore complex

QSAR:

Quantitative structure activity relationship

RBC:

Sheep red blood cell

RSR:

Ribotoxic stress response

SAR:

Structure–activity relationships

SMI:

Mall molecule inhibitors

SRC:

Steroid receptor coactivator

TCN:

Trichothecin

TLR:

Toll-like Receptors

TPA:

12-O-tetradecanoylphorbol-13-acetate

TRAIL:

TNF-related apoptosis-inducing ligand

TRPA1:

Transient receptor potential ankyrin-1

VA:

Verrucarins A

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 31602114 and 31572575), the Yangtze Fund for Youth Teams of Science and Technology Innovation (2016cqt02), the Fundamental Research Funds for the Central Universities (2662016PY115), and the project of long-term development plan UHK.

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Correspondence to Qinghua Wu or Kamil Kuca.

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Wu, Q., Wang, X., Nepovimova, E. et al. Trichothecenes: immunomodulatory effects, mechanisms, and anti-cancer potential. Arch Toxicol 91, 3737–3785 (2017). https://doi.org/10.1007/s00204-017-2118-3

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Keywords

  • T-2 toxin
  • Deoxynivalenol
  • Immunomodulation
  • Anti-cancer
  • Signaling pathway
  • Autophagy
  • Immune evasion