American Association for Cancer Research
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Figure S7 from Drug Targeting the Actin Cytoskeleton Potentiates the Cytotoxicity of Low Dose Vincristine by Abrogating Actin-Mediated Repair of Spindle Defects

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posted on 2023-04-03, 17:50 authored by Yao Wang, Jeffrey H. Stear, Ashleigh Swain, Xing Xu, Nicole S. Bryce, Michael Carnell, Irina B. Alieva, Vera B. Dugina, Timothy P. Cripe, Justine Stehn, Edna C. Hardeman, Peter W. Gunning

Representative images of spindle phenotypes.

Funding

Australian Research Council

NHMRC

The Kid's Cancer Project

RFBR

History

ARTICLE ABSTRACT

Antimicrotubule vinca alkaloids are widely used in the clinic but their toxicity is often dose limiting. Strategies that enhance their effectiveness at lower doses are needed. We show that combining vinca alkaloids with compounds that target a specific population of actin filaments containing the cancer-associated tropomyosin Tpm3.1 result in synergy against a broad range of tumor cell types. We discovered that low concentrations of vincristine alone induce supernumerary microtubule asters that form transient multi-polar spindles in early mitosis. Over time these asters can be reconstructed into functional bipolar spindles resulting in cell division and survival. These microtubule asters are organized by the nuclear mitotic apparatus protein (NuMA)–dynein–dynactin complex without involvement of centrosomes. However, anti-Tpm3.1 compounds at nontoxic concentrations inhibit this rescue mechanism resulting in delayed onset of anaphase, formation of multi-polar spindles, and apoptosis during mitosis. These findings indicate that drug targeting actin filaments containing Tpm3.1 potentiates the anticancer activity of low-dose vincristine treatment. Simultaneously inhibiting Tpm3.1-containing actin filaments and microtubules is a promising strategy to potentiate the anticancer activity of low-dose vincristine.