Anti-cancer activities of cytokinin ribosides

Abstract

Cytokinins are plant hormones and play essential roles in regulating plant growth and development. They also have diverse pharmacological effects in animals and humans. Whereas cytokinin bases have been studied mainly for their cytoprotective activities, cytokinin ribosides have been explored as anti-cancer agents. Cytokinin ribosides inhibit growth or cause apoptosis in various cell lines derived from diverse malignancies including those with a mutant p53 gene. Activity against cancer stem cells, anti-angiogenic activity, and the ability to stimulate an immune response to malignant cells have been reported as well. There are also positive results from in vivo studies and reports of activity in patients with hematological malignancies and solid tumors. Here, we review studies of the anti-cancer activity of cytokinin ribosides since the 1960s and comment on the issues that need to be addressed for the further development of cytokinin ribosides into anti-cancer drugs.

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Fig. 1

Notes

  1. 1.

    Full names of the proteins encoded by transcripts identified in the microarray experiment of Colombo et al. (2009) are as follows: AXIN1—AXIN1, CERK—ceramide kinase, DDIT3—DNA damage-inducible transcript 3, DUSP16—dual specificity protein phosphatase 16, EIF2AK3—eukaryotic translation initiation factor 2-alpha kinase 3, ERN1—endoplasmic reticulum to nucleus signalling 1, HBP1—HMG-box transcription factor 1, JMY—junction-mediating and regulatory protein, MBIP—MAP3K12 binding inhibitory protein 1, PPP1R15A—protein phosphatase 1 regulatory subunit 15A, SESN2—sestrin-2, TRAF6—TNF receptor associated factor 6 and TRIB1—tribbles homolog 1.

  2. 2.

    The adenosine receptors are G protein-coupled membrane receptors with adenosine as endogenous ligand. Adenosine arises from dephosphorylation of both intracellular and extracellular ATP. Its production is increased under stress, and increased concentrations occur in various disorders. There are four types in humans—A1, A2A, A2B, and A3 (Fredholm et al. 2000). Their ligands have been studied as candidate drugs for a wide range of disorders including chronic heart failure, sickle cell anemia, Parkinson disease, autoimmune diseases, and cancers. A2A and A3 receptors are promising targets for cancer therapy. A2A receptor antagonists suppress immune system evasion by cancer cells. A3 receptor agonists have antiproliferative and proapoptotic effects. A3 agonist namodenoson and A2A antagonists preladenant (MK-3814), PBF-509, CPI-444, and AZD4635 are being evaluated in clinical trials (Merighi et al. 2019). Some N6-substituted adenosines are potent A1 agonists {e.g. tecadenoson—N-[3-(R)-tetrahydrofuranyl]-6-aminopurine riboside and selodenoson—N-5′-ethyl-N6-(cyclopentyl)adenosine} and A3 agonists {e.g. namodesone/Cl-IB-MECA/-[2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyl-uronamide]} (Jacobson and Müller 2016). The natural CKRs are much weaker inhibitors making their further development into adenosine receptor targeting drugs improbable in our opinion.

Abbreviations

A3R:

Adenosine receptor A3

ADA:

Adenosine deaminase

ADK:

Adenosine kinase

AMPK:

AMP-activated protein kinase

BAR:

N6-benzyladenosine

BAR5′MP:

N6-benzyladenosine-5′-monophosphate

CKR:

Cytokinin riboside

CKR5′MP:

Cytokinin riboside-5′-monophosphate

DNPH1:

2′-Deoxynucleoside 5′-phosphate N-hydrolase 1

FPPS:

Farnesyl pyrophosphate synthase

iPR:

N6-isopentenyladenosine

iPR5′MP:

N6-isopentenyladenosine-5′-monophosphate

KR:

Kinetin riboside

KR5′TP:

Kinetin riboside-5′-triphosphate

2OH3MeOBAR:

N6-(2-hydroxy-3-methoxybenzyl)adenosine

oTR:

Ortho-topolin riboside

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Acknowledgements

This study was partially supported by the Ministry of Education, Youth and Sports of the Czech Republic (GACR Grant Nos. 17-14007S, NPU I LO1304, and OP VVV project ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868).

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Voller, J., Béres, T., Zatloukal, M. et al. Anti-cancer activities of cytokinin ribosides. Phytochem Rev 18, 1101–1113 (2019). https://doi.org/10.1007/s11101-019-09620-4

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Keywords

  • Cytokinin
  • Cytokinin riboside
  • Cancer
  • Anti-cancer drug