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Article

Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models

1
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Floyd Curl Drive, San Antonio, TX 78229, USA
2
Mays Cancer Center, 7979 Wurzbach Road, San Antonio, TX 78229, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Nadine Kretschmer and Raffaele Capasso
Molecules 2021, 26(13), 4077; https://doi.org/10.3390/molecules26134077
Received: 12 May 2021 / Revised: 23 June 2021 / Accepted: 30 June 2021 / Published: 3 July 2021
Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients. View Full-Text
Keywords: microtubule stabilizers; taxanes; drug resistance; natural products; ovarian cancer; metastasis; covalent drugs; anticancer agents; murine model microtubule stabilizers; taxanes; drug resistance; natural products; ovarian cancer; metastasis; covalent drugs; anticancer agents; murine model
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MDPI and ACS Style

Yee, S.S.; Risinger, A.L. Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models. Molecules 2021, 26, 4077. https://doi.org/10.3390/molecules26134077

AMA Style

Yee SS, Risinger AL. Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models. Molecules. 2021; 26(13):4077. https://doi.org/10.3390/molecules26134077

Chicago/Turabian Style

Yee, Samantha S., and April L. Risinger 2021. "Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models" Molecules 26, no. 13: 4077. https://doi.org/10.3390/molecules26134077

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