Xing Xu1, Yao Wang1, Nicole S Bryce1, Katrina Tang2, Nicola S Meagher3,4, Eun Young Kang5, Linda E Kelemen6, Martin Köbel5, Susan J Ramus3,4, Michael Friedlander7, Caroline E Ford3,4, Edna C Hardeman1,4, Peter W Gunning8,9. 1. School of Medical Sciences, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia. 2. Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, NSW, Australia. 3. School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia. 4. Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia. 5. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada. 6. South Carolina Department of Health and Environmental Control, North Charleston, SC, USA. 7. Prince of Wales Clinical School UNSW and Department of Medical Oncology, The Prince of Wales Hospital, Sydney, NSW, Australia. 8. School of Medical Sciences, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia. p.gunning@unsw.edu.au. 9. Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia. p.gunning@unsw.edu.au.
Abstract
BACKGROUND: Anti-microtubule agents are widely used to treat ovarian cancers, but the efficacy is often compromised by drug resistance. We investigated co-targeting the actin/tropomyosin cytoskeleton and microtubules to increase treatment efficacy in ovarian cancers and potentially overcome resistance. METHODS: The presence of tropomyosin-3.1 (Tpm3.1) was examined in clinical specimens from ovarian cancer patients using immunohistochemistry. Combinatorial effects of an anti-Tpm3.1 compound, ATM-3507, with vinorelbine and paclitaxel were evaluated in ovarian cancer cells via MTS and apoptosis assays. The mechanisms of action were established using live- and fixed-cell imaging and protein analysis. RESULTS: Tpm3.1 is overexpressed in 97% of tumour tissues (558 of 577) representing all histotypes of epithelial ovarian cancer. ATM-3507 displayed synergy with both anti-microtubule agents to reduce cell viability. Only vinorelbine synergised with ATM-3507 in causing apoptosis. ATM-3507 significantly prolonged vinorelbine-induced mitotic arrest with elevated activity of the spindle assembly checkpoint and mitotic cell death; however, ATM-3507 showed minor impact on paclitaxel-induced mitotic defects. Both combinations substantially increased post-mitotic G1 arrest with cyclin D1 and E1 downregulation and an increase of p21Cip and p27Kip. CONCLUSION: Combined targeting of Tpm3.1/actin and microtubules is a promising treatment strategy for ovarian cancer that should be further tested in clinical settings.
BACKGROUND: Anti-microtubule agents are widely used to treat ovarian cancers, but the efficacy is often compromised by drug resistance. We investigated co-targeting the actin/tropomyosin cytoskeleton and microtubules to increase treatment efficacy in ovarian cancers and potentially overcome resistance. METHODS: The presence of tropomyosin-3.1 (Tpm3.1) was examined in clinical specimens from ovarian cancer patients using immunohistochemistry. Combinatorial effects of an anti-Tpm3.1 compound, ATM-3507, with vinorelbine and paclitaxel were evaluated in ovarian cancer cells via MTS and apoptosis assays. The mechanisms of action were established using live- and fixed-cell imaging and protein analysis. RESULTS: Tpm3.1 is overexpressed in 97% of tumour tissues (558 of 577) representing all histotypes of epithelial ovarian cancer. ATM-3507 displayed synergy with both anti-microtubule agents to reduce cell viability. Only vinorelbine synergised with ATM-3507 in causing apoptosis. ATM-3507 significantly prolonged vinorelbine-induced mitotic arrest with elevated activity of the spindle assembly checkpoint and mitotic cell death; however, ATM-3507 showed minor impact on paclitaxel-induced mitotic defects. Both combinations substantially increased post-mitotic G1 arrest with cyclin D1 and E1 downregulation and an increase of p21Cip and p27Kip. CONCLUSION: Combined targeting of Tpm3.1/actin and microtubules is a promising treatment strategy for ovarian cancer that should be further tested in clinical settings.
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