Abstract
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.
Original language | English (US) |
---|---|
Article number | 4077 |
Journal | Molecules |
Volume | 26 |
Issue number | 13 |
DOIs | |
State | Published - Jul 1 2021 |
Keywords
- Anticancer agents
- Covalent drugs
- Drug resistance
- Metastasis
- Microtubule stabilizers
- Murine model
- Natural products
- Ovarian cancer
- Taxanes
ASJC Scopus subject areas
- Drug Discovery
- Analytical Chemistry
- Chemistry (miscellaneous)
- Molecular Medicine
- Physical and Theoretical Chemistry
- Pharmaceutical Science
- Organic Chemistry