SQ1274, a novel microtubule inhibitor, inhibits ovarian and uterine cancer cell growth

• Published in: Gynecologic oncology Vol. 151; no. 2; pp. 337 - 344
• Main Authors: Mills, Kathryn A., Roach, S. Tanner, Quinn, Jeanne M., Guo, Lei, Beck, Hollie M., Lomonosova, Elena, Ilivicky, Anna R., Starks, Courtney M., Lawrence, Julie A., Hagemann, Andrea R., McCourt, Carolyn, Thaker, Premal H., Powell, Matthew A., Mutch, David G., Fuh, Katherine C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2018
• Subjects: Animals; Apoptosis - drug effects; Carcinoma, Ovarian Epithelial; Cell Cycle - drug effects; Cell Growth Processes - drug effects; Cell Line, Tumor; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Female; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Paclitaxel - pharmacology; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Receptor Protein-Tyrosine Kinases - biosynthesis; Receptor Protein-Tyrosine Kinases - genetics; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Tubulin Modulators - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2018.08.008

Paclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer. This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo. We assessed the sensitivity of ovarian (OVCAR8) and uterine (ARK1) cancer cell lines to SQ1274 and paclitaxel using XTT assays. We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel. Differences in cell-cycle arrest and apoptosis were investigated using flow cytometry. Finally, we treated ovarian and uterine xenograft models with vehicle, paclitaxel, or SQ1274. First, we demonstrate that SQ1274 has a much lower IC50 than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines. Second, we show SQ1274 decreases both RNA and protein expression of AXL. Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel. Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel. SQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer. This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer. •SQ1274, a colchicine-binding site inhibitor, is a viable alternative to paclitaxel in treating ovarian and uterine cancer.•SQ1274 has a much lower IC50 than paclitaxel in both ovarian and uterine cancer.•SQ1274 decreases both RNA and protein expression of AXL.•SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel.•SQ1274 effectively prevents tumor growth in vivo.