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

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 4077
Author(s):  
Samantha S. Yee ◽  
April L. Risinger
Keyword(s):  
Ovarian Cancer ◽  
Acquired Resistance ◽  
Disease Model ◽  
Intraperitoneal Administration ◽  
Metastatic Progression ◽  
Clinical Prognosis ◽  
Microtubule Stabilization ◽  
Cancer Models

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.

scholarly journals An In Vitro and In Vivo Investigation of the Antimetastatic Effects of a Chinese Medicinal Decoction, Erxian Decoction, on Human Ovarian Cancer Models

2012 ◽  
Vol 12 (4) ◽  
pp. 336-346 ◽  
Author(s):  
Ellie S. M. Chu ◽  
Stephen C. W. Sze ◽  
Ho P. Cheung ◽  
Qing Liu ◽  
Tzi B. Ng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Human Ovarian Cancer ◽  
Erxian Decoction ◽  
Cancer Models

Abstract 1525: SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo

2018 ◽  
Author(s):  
Panagiotis A. Konstantinopoulos ◽  
Graeme Hodgson ◽  
Nisha Rajagopal ◽  
Liv Johannessen ◽  
Joyce F. Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Cancer Models

scholarly journals Inhibition of Inhibitor of Nuclear Factor-κB Phosphorylation Increases the Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models

2004 ◽  
Vol 10 (22) ◽  
pp. 7645-7654 ◽  
Author(s):  
Seiji Mabuchi ◽  
Masahide Ohmichi ◽  
Yukihiro Nishio ◽  
Tadashi Hayasaka ◽  
Akiko Kimura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Cancer Models

scholarly journals Src Inhibition with Saracatinib Reverses Fulvestrant Resistance in ER-Positive Ovarian Cancer Models In Vitro and In Vivo

2012 ◽  
Vol 18 (21) ◽  
pp. 5911-5923 ◽  
Author(s):  
Fiona Simpkins ◽  
Pedro Hevia-Paez ◽  
Jun Sun ◽  
Wendy Ullmer ◽  
Candace A. Gilbert ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Models ◽  
Er Positive

scholarly journals Quinacrine Induces Nucleolar Stress in Treatment-Refractory Ovarian Cancer Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4645
Author(s):  
Derek B. Oien ◽  
Upasana Ray ◽  
Christopher L. Pathoulas ◽  
Ling Jin ◽  
Prabhu Thirusangu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Gynecologic Cancer ◽  
Acquired Resistance ◽  
Disease Recurrence ◽  
Parp Inhibition ◽  
Nucleolar Stress ◽  
Treatment Refractory

A considerable subset of gynecologic cancer patients experience disease recurrence or acquired resistance, which contributes to high mortality rates in ovarian cancer (OC). Our prior studies showed that quinacrine (QC), an antimalarial drug, enhanced chemotherapy sensitivity in treatment-refractory OC cells, including artificially generated chemoresistant and high-grade serous OC cells. In this study, we investigated QC-induced transcriptomic changes to uncover its cytotoxic mechanisms of action. Isogenic pairs of OC cells generated to be chemoresistant and their chemosensitive counterparts were treated with QC followed by RNA-seq analysis. Validation of selected expression results and database comparison analyses indicated the ribosomal biogenesis (RBG) pathway is inhibited by QC. RBG is commonly upregulated in cancer cells and is emerging as a drug target. We found that QC attenuates the in vitro and in vivo expression of nucleostemin (NS/GNL3), a nucleolar RBG and DNA repair protein, and the RPA194 catalytic subunit of Pol I that results in RBG inhibition and nucleolar stress. QC promotes the redistribution of fibrillarin in the form of extranuclear foci and nucleolar caps, an indicator of nucleolar stress conditions. In addition, we found that QC-induced downregulation of NS disrupted homologous recombination repair both by reducing NS protein levels and PARylation resulting in reduced RAD51 recruitment to DNA damage. Our data suggest that QC inhibits RBG and this inhibition promotes DNA damage by directly downregulating the NS–RAD51 interaction. Additionally, QC showed strong synergy with PARP inhibitors in OC cells. Overall, we found that QC downregulates the RBG pathway, induces nucleolar stress, supports the increase of DNA damage, and sensitizes cells to PARP inhibition, which supports new therapeutic stratagems for treatment-refractory OC. Our work offers support for targeting RBG in OC and determines NS to be a novel target for QC.

scholarly journals Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo Zhou ◽  
Meng Xia ◽  
Bin Wang ◽  
Niresh Thapa ◽  
Lijuan Gan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Annexin V ◽  
Therapy Resistance ◽  
Tumor Xenograft ◽  
Cancer Cell Growth ◽  
Cisplatin Therapy

Abstract Background Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. Results We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. Conclusion Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

Effect of a topoisomerase-1 inhibitor (topotecan) on the efficacy of cisplatin in in vitro and in vivo platinum-resistant ovarian cancer models.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e13160-e13160
Author(s):  
S. Tsunetoh ◽  
Y. Terai ◽  
H. Sasaki ◽  
Y. Tanaka ◽  
T. Sekijima ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Topoisomerase 1 ◽  
Platinum Resistant ◽  
Cancer Models
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