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Nuclear factor-κB inhibitors as sensitizers to anticancer drugs

Nature Reviews Cancer volume 5, pages 297–309 (2005)Cite this article

Key Points

  • Many anticancer agents induce nuclear factor-κB (NF-κB) nuclear translocation and activation of its target genes, which impinge on cellular resistance to anticancer agents.

  • Many malignant tumours display constitutive NF-κB activation that allows malignant cells to escape apoptosis.

  • NF-κB inhibition prevents tumour resistance to chemotherapeutic agents, so development of NF-κB inhibitors could increase the efficacy of many anticancer agents.

  • Several NF-κB inhibitors, such as proteasome inhibitors, BAY 11-7085, BAY 11-7082, soy isoflavone genistein, parthenolide, CHS 828, flavopiridol and gliotoxin, enhance the cytotoxic effect of anticancer agents.

  • It has also been demonstrated that steroids and non-steroidal anti-inflammatory drugs, such as cyclooxygenase-2 inhibitors, block NF-κB activation.

Abstract

The cytotoxicity of chemotherapeutic agents is attributed to apoptosis. Acquired resistance to the effects of chemotherapy has emerged as a significant impediment to effective cancer therapy. One feature that cytotoxic treatments of cancer have in common is their activation of the transcription factor nuclear factor-κB (NF-κB), which regulates cell survival. NF-κB activation suppresses the apoptotic potential of chemotherapeutic agents and contributes to resistance. What evidence is there that inhibitors of NF-κB might promote apoptosis in cancer cells and can NF-κB inhibitors be used to overcome resistance to chemotherapeutic agents?

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Figure 1: A scheme of the nuclear factor-κB pathway activated by anticancer drugs.
Figure 2: Nuclear factor-κB inhibition and apoptosis.
Figure 3: Constitutive activation of nuclear factor-κB in cancer cells.

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Acknowledgements

We thank N. Aoki and N. Kanamoto for kind help. This work was supported by a grant for optimization of new anticancer drugs from the Health and Labour Sciences Research Grants of Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare.

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Authors and Affiliations

  1. Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyoku, Tokyo, 113-8677, Japan

    Chikashi Nakanishi & Masakazu Toi

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  1. Chikashi Nakanishi
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DATABASES

Entrez Gene

AKT

BCL-XL

BFL1

CD44

CDC25A

CDC25C

COX2

CYLD

ELKS

FKBP51

IκBα

IKKα

IKKβ

IKKγ

IL-1

ING4

JUN

MDM2

MDR1

MEKK1

MMP2

MMP9

MYC

NF-κB1

NF-κB2

p21

p27

p53

REL

RELA

RELB

TNFα

OMIM

familial cylindromatosis

Glossary

ANKYRIN REPEAT

A repeating sequence of 30–33 amino acids that is found in the ankyrin protein. The ankyrin repeat of IκB proteins is required for association with the nuclear localization signal of NF-κB proteins.

PROTEASOME

A 26S multiprotein complex that catalyses the breakdown of polyubiquitylated proteins.

COLITIS-ASSOCIATED CANCER

Colitis-associated cancer arises in patients with inflammatory bowel disease, particularly ulcerative colitis. The risk of colorectal cancer in patients with ulcerative colitis 20 years after the initial diagnosis is estimated to be between 5% and 10%.

CYCLOOXYGENASE-2

Cyclooxygenase-2 (COX2) is the enzyme that normally synthesizes prostaglandins during an inflammatory response. Proinflammatory and mitogenic stimuli, such as growth factors and cytokines, induce COX2 and many tumours express COX2.

UBIQUITIN

A 76-amino-acid polypeptide that is highly conserved in eukaryotic cells. The ubiquitin system is a conserved complex that marks old or defective proteins for cleavage.

OFF-TARGET EFFECT

This term is used to describe the effect of a drug on another protein, molecule or complex that is different from the protein that it is known to effect or originally designed to effect.

PYRIDYL CYANOGUANIDINE

Pyridyl cyanoguanidines are potassium-channel openers. Pinacidil (N-1,2,2-trimethylpropyl-N-cyano-N′-4-pyridylguanidine) is a structural prototype with potent antihypertensive activity. Replacement of the side chain of pinacidil by longer aryl-containing side chains give rise to compounds with increasing antitumour activity but without antihypertensive activity.

ELKS

ELKS is a 105-kDa IKK regulatory subunit protein. The name ELKS is derived from the relative abundance of its constitutive amino acids: glutamic acid (E), leucine (L), lysine (K) and serine (S). The function of ELKS is probably to recruit IκBα to the IKK complex.

MACROLIDES

A group of antibiotics produced by various strains of Streptomyces that have a complex macrocyclic structure. They inhibit protein synthesis by blocking the 50S ribosomal subunit and include erythromycin and carbomycin.

IMMUNOPHILINS

Receptors for immunosuppressive drugs such as cyclosporin A and rapamycin. Drug– immunophilin complexes suppress the immune response.

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Nakanishi, C., Toi, M. Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5, 297–309 (2005). https://doi.org/10.1038/nrc1588

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