A novel class of anticancer compounds targets the actin cytoskeleton in tumor cells.
The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers.
School of Medical Sciences, University of New South Wales, Australia.
Justine R
JR
Stehn
Nikolas K
NK
Haass
Teresa
T
Bonello
Melissa
M
Desouza
Gregg
G
Kottyan
Herbert
H
Treutlein
Jun
J
Zeng
Paula R B B
PR
Nascimento
Vanessa B
VB
Sequeira
Tanya L
TL
Butler
Munif
M
Allanson
Thomas
T
Fath
Timothy A
TA
Hill
Adam
A
McCluskey
Galina
G
Schevzov
Stephen J
SJ
Palmer
Edna C
EC
Hardeman
David
D
Winlaw
Vivienne E
VE
Reeve
Ian
I
Dixon
Wolfgang
W
Weninger
Timothy P
TP
Cripe
Peter W
PW
Gunning
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy; D014335:Tropomyosin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D014335:Tropomyosin