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. 2013 Jul 1;18(3):368–397. doi: 10.2478/s11658-013-0094-z

Tubulin-interactive stilbene derivatives as anticancer agents

Renata Mikstacka 1,✉, Tomasz Stefański 1, Jakub Różański 1
PMCID: PMC6275897  PMID: 23818224

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.

Key words: Tubulin polymerization, Tubulin-interactive agents, Stilbenes, Combretastatins

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Abbreviations used

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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