A novel class of anticancer compounds targets the actin cytoskeleton in tumor cells

Justine Stehn, Nikolas K Haass, Theresa Bonello, Melissa Desouza, Gregg Kottyan, H R Treutlein, Jun Zeng, Paula R B B Nascimento, Vanessa B Sequeira, Tanya L Butler, Munif Allanson, Thomas Fath, Tim Hill, Adam McCluskey, Galina Schevzov, Stephen J Palmer, Edna Christine Hardeman, David S Winlaw, Vivienne E Reeve, Ian DixonWolfgang Weninger, Timothy P Cripe, Peter William Gunning

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98 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)5169 - 5182
Number of pages14
JournalCancer Research
Volume73
Issue number16
DOIs
Publication statusPublished - 2013

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