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Tubulin-interactive stilbene derivatives as anticancer agents

Abstract

Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

Abbreviations

AIA:

angiogenesis-inhibiting agents

BAD:

Bcl-2-associated death promoter

Bcl-2:

B-cell lymphoma 2

Bcl-xl:

B-cell lymphoma extra large

CA-1:

combretastatin A-1

CA-2:

combretastatin A-2

CA-3:

combretastatin A-3

CA-4:

combretastatin A-4

CA-1P:

combretastatin A-1 diphosphate, OXi4503

CA-4P:

combretastatin A-4 phosphate, Zybrestat

CB-1:

combretastatin B-1

CB-2:

combretastatin B-2

CDC2:

cell division control protein 2

CDK1:

cyclin-dependent kinase 1

CoMFA:

comparative molecular field analysis

DAMA-colchicine:

N-deacetyl-N-(2-mercaptoacetyl)-colchicine

ERK:

extracellular signal-regulated kinase

GTP:

guanosine-5′-triphosphate

GDP:

guanosine-5′-diphosphate

HIF-1α:

hypoxiainducible factor 1α

HNSCC:

head and neck squamous cell carcinoma

HUVECs:

human umbilical vein endothelial cells

iNOS:

inducible nitric oxide synthase

JNK:

c-Jun N-terminal kinase

LY290181:

2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)pyran-3-carbonitrile

MAPs:

microtubule-associated proteins

MAPKs:

mitogen-activated protein kinases

MIA:

microtubule-interfering agents

MRP-1:

multidrug resistance protein 1

MRP-3:

multidrug resistance protein 3

SAR:

structure-activity relationship

SPA:

Special Protocol Assessment

+TIPs:

plus-and-tracking proteins

VDAs:

vascular disrupting agents

VEGF:

vascular endothelial growth factor

VEGFR2:

VEGF receptor 2

VTAs:

vascular targeting agents

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Mikstacka, R., Stefański, T. & Różański, J. Tubulin-interactive stilbene derivatives as anticancer agents. Cell Mol Biol Lett 18, 368–397 (2013). https://doi.org/10.2478/s11658-013-0094-z

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Key words

  • Tubulin polymerization
  • Tubulin-interactive agents
  • Stilbenes
  • Combretastatins