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. IMPLICATIONS: Simultaneously inhibiting Tpm3.1-containing actin filaments and microtubules is a promising strategy to potentiate the anticancer activity of low-dose vincristine.
Highlights
Combination therapy has shown promise for cancer treatment by reducing individual drug dosage while maintaining or increasing overall treatment efficacy [1,2,3,4,5,6,7,8,9]
Our results demonstrate that the synergy of vincristine in combination with anti-Tpm3.1 compounds is very strong across a wide range of cancer types in vitro and a xenograft model of lung cancer
Our study reveals that the mechanism of drug synergy is primarily due to the suppression by anti-Tpm3.1 drugs of an intrinsic rescue response that normally corrects spindle defects and promotes mitotic progression in the presence of vincristine alone at low concentrations
Summary
Combination therapy has shown promise for cancer treatment by reducing individual drug dosage while maintaining or increasing overall treatment efficacy [1,2,3,4,5,6,7,8,9]. Because antimicrotubule (anti-MT) chemotherapeutics are used as first-line and/or relapse treatment in up to half of all patients with cancer, and have toxic and often long-lasting side effects at therapeutic doses [14], identifying compounds that synergize with anti-MTs especially at low concentrations [15] represents a significant advance for current therapies. To improve the efficacy of anti-MT treatment, we established a synergistic combination regime designed on the interplay between the microtubule network and the actin cytoskeleton in promoting cell growth [16, 17]. This regime combines the anti-MT drugs vincristine. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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