Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells
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Shaoyu Wu1,2,3, Zhijian Guo4, Chad D. Hopkins5, Ning Wei1,2, Edward Chu1,2, Peter Wipf2,5, John C. Schmitz1,2
1Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA
2Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
3Department of Chemistry, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China
4Department of Nephrology, NanFang Hospital, Southern Medical University, Guangzhou 510515, China
5Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
John C. Schmitz, e-mail: [email protected]
Keywords: tubulin polymerization, disorazole, human colorectal cancer
Received: July 15, 2015 Accepted: September 28, 2015 Published: October 19, 2015
The novel, chemically stabilized disorazole analog, (-)-CP2-disorazole C1 (1) displayed potent anti-proliferative activity against a broad-spectrum of human colorectal cancer cells. HCT15 and H630R1 cell lines expressing high basal levels of the ABCB1 protein, known to cause multi-drug resistance, were also sensitive to growth inhibition by 1 but were resistant to both vincristine and docetaxel, two commonly used microtubule inhibitors. Compound 1 exhibited strong inhibition of tubulin polymerization at a level comparable to vincristine. In addition, treatment with 1 resulted in decreased protein levels of β-tubulin but not α-tubulin. An analysis of cellular proteins known to interact with microtubules showed that 1 caused decreased expression of c-Myc, APC, Rb, and additional key cellular signaling pathways in CRC cells. Treatment with compound 1 also resulted in G2/M cell cycle arrest and induction of apoptosis, but not senescence. Furthermore, endothelial spheroid sprouting assays demonstrated that 1 suppressed angiogenesis and can, therefore, potentially prevent cancer cells from spreading and metastasizing. Taken together, these findings suggest that the microtubule disruptor 1 may be a potential drug candidate for the treatment of mCRC.
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