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.
Highlights
The idea of targeting the actin cytoskeleton is not new, given its role in cellular transformation and biologic processes such as cell division and cell migration [1,2,3,4]
Using melanoma and neuroblastoma mouse xenograft models, we have shown that TR100 is effective in reducing tumor cell growth in vivo without compromising cardiac function
Tropomyosin is an important regulator of the actin cytoskeleton [9, 42] and a key component of the actin microfilaments in tumor cells [1, 43]
Summary
The idea of targeting the actin cytoskeleton is not new, given its role in cellular transformation and biologic processes such as cell division and cell migration [1,2,3,4]. It is surprising that there are still no anti-actin compounds used in current chemotherapy [5]. The primary reason for this is the inability of existing anti-actin agents to discriminate between. Authors' Affiliations: 1School of Medical Sciences, University of New South Wales; 2Faculty of Veterinary Science, University of Sydney, Sydney; 3Centenary Institute, Newtown; 4Discipline of Dermatology, University of Sydney, Camperdown; 5Kids Heart Research, The Children's Hospital at Westmead, Westmead; 6Chemistry, School of Environmental & Life Sciences, University of Newcastle, Callaghan, New South Wales; 7The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland; 8Qubist Molecular Design Pty Ltd and Monash Institute of Pharmaceutical Sciences, Monash University, Parkville; 9Genscreen Pty Ltd, Melbourne, Victoria, Australia; and 10Division of Oncology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio. Cripe: Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH
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