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Natural Compounds as Specific Inhibitors of Cyclin-Dependent Kinases – Past, Present and Future

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Natural compounds as inducers of cell death

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Abstract

Deregulation of the cell cycle is one of the first events during malignant transformations that convert normal cells into tumor cells. Cyclin-dependent kinases (CDKs) are key elements of the mammalian genome surveillance machinery that controls the cell cycle. Their activity (which is normally regulated via cyclin binding, phosphorylation events and interactions with endogenous inhibitors of CDKs, CKIs) is frequently altered in human cancers. Therefore, strenuous efforts are being made to develop means to counter cell cycle malfunctions using pharmacological inhibitors of CDKs.

Many of the most promising CDK inhibitors originate from natural sources, e. g. flavopiridol, staurosporine, indirubin and olomoucine. More selective and less cytotoxic analogues have also been developed, based on their chemical structures, that have anti-cancer potential operating through several mechanisms, including modulation of the cell cycle, transcription and apoptosis in cancer cells. Some of the CDK inhibitors derived from natural compounds or their analogues are in clinical trials or already in use. Considering the huge numbers of compounds in plant species (∼300,000), which might include powerful, as yet unidentified anti-cancer agents, it seems reasonable to assume that that even more potent and selective CDK inhibitors will be discovered and characterized in the future.

Margarita Maurer and Oxana Komina both of these authors equally contributed to the work

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Abbreviations

Bcl-2:

B-cell lymphoma 2

CAK:

CDK-activating kinase

CDK:

cyclin-dependent kinase

Chk1:

checkpoint kinase 1

CKI:

cyclin-dependent kinase inhibitor

CLL:

chronic lymphocytic leukemia

c-myc:

cellular homolog of avian myelocytomatosis virus oncogene

CTD:

carboxy-terminal domain

DRB:

5,6-dichlorobenzimidazole 1-β-D-ribofuranoside

DSIF:

DRB sensitivity-inducing factor

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

EMA:

European Medicines Agency

GSK3 β:

glycogen synthase kinase 3 β

IAPs:

inhibitors of apoptosis

MAT1:

ménage-a-trois

Mcl-1:

myeloid cell leukemia sequence 1

MDR:

multi-drug resistance

NELF:

negative elongation factor

NF-κB:

nuclear factor-κB

p53AIP-1:

p53 apoptosis-inducing protein 1

PARP-1:

poly(ADP-ribose) polymerase-1

PKA:

protein kinase A

PKC:

protein kinase C

pRb:

retinoblastoma

P-TEFb:

positive transcription elongation factor b

XIAP:

X-linked inhibitor of apoptosis

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Acknowledgments

This review is based on research carried out over several years, during which the authors have been supported by grants from the Austrian Funding Agency FWF (No. P19894-B11) and the Austrian Academy of Science (OEAW) (project No. AP00401OFF).

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  1. Cell Cycle Regulation Group, Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria

    Margarita Maurer, Oxana Komina & Józefa Węsierska-Gądek

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  1. Margarita Maurer
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Maurer, M., Komina, O., Węsierska-Gądek, J. (2012). Natural Compounds as Specific Inhibitors of Cyclin-Dependent Kinases – Past, Present and Future. In: Diederich, M., Noworyta, K. (eds) Natural compounds as inducers of cell death. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4575-9_14

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