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

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.

Epithelial Ovarian Cancer: A Five Year Review

“…The mode of action of cisplatin depends on mitophagy and p62 regulation. In the study by Yee S. S. et al [ 40 ], covalent microtubule stabilizers, i.e., the C-22,23-epoxytaccalonolides, were evaluated. Taccalonolide AF was observed to have efficacy in taxane-resistant ovarian cancer models in vitro and in vivo.…”

In Vivo Evaluation of (−)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site

“…This would be relevant to the in vivo situation where the drug is actively cleared. Moreover, a strong degree of cellular persistence following the removal of excess drug from the medium has been associated with potent in vivo antitumor efficacy for other classes of microtubule binding drugs, including eribulin and the taccalonolides [15,20]. To evaluate cellular persistence in vitro, we treated MDA-MB-231 cells at a low density with 10 or 50 nM zampanolide or paclitaxel for 2 h after which the drug containing media is washed off and replaced allowing cells to grow into colonies without any exogenous drug for an additional 10 days.…”

“…The C22,23-epoxytaccalonolides also bind covalently to β-tubulin [12] to promote microtubule stabilization with in vitro potency similar to the taxanes, leading to antimitotic and cytotoxic effects [13,14]. While the taccalonolides retain efficacy in taxane-resistant models both in vitro and in vivo, they have a narrow therapeutic index with systemic administration [9,15]. In spite of their shared covalent binding to β-tubulin [9,16] these drugs have distinct effects on microtubule stabilization; zampanolide stabilizes the M-loop of β-tubulin in a manner similar to paclitaxel while taccalonolide and cyclostreptin binding is not associated with M-loop stabilization [9,13,14].…”

Baohuoside I inhibits resistance to cisplatin in ovarian cancer cells by suppressing autophagy via downregulating HIF‐1α/ATG5 axis

“…2 The majority of patients still suffer from progressive and recurrent ovarian cancer owing to chemotherapy resistance, despite tremendous advances in understanding the pathogenic underpinnings of disease. 3 Multiple variables have been implicated in the regulation of cisplatin (DDP) resistance in the past. 4 The search for novel agents that sensitive ovarian cancer cells to DDP is, therefore, of critical relevance.…”

“…Nowadays, the most common methods of treating ovarian cancer are chemotherapy and cytoreductive surgery; however, the therapeutic effect remains unsatisfactory 2 . The majority of patients still suffer from progressive and recurrent ovarian cancer owing to chemotherapy resistance, despite tremendous advances in understanding the pathogenic underpinnings of disease 3 . Multiple variables have been implicated in the regulation of cisplatin (DDP) resistance in the past 4 .…”