Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells.

Abstract

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.

• Authors: Shaoyu Wu, Zhijian Guo, Chad D Hopkins, Ning Wei, Edward Chu, Peter Wipf, John C Schmitz
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 38 Pg. 40866-79 (Dec 01 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26506423 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• Macrolides
• Oxazoles
• Tubulin Modulators
• disorazole C1

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Drug Resistance, Multiple (drug effects)
• Fluorescent Antibody Technique
• Humans
• Immunoenzyme Techniques
• Macrolides (pharmacology)
• Microtubules (chemistry, drug effects)
• Oxazoles (pharmacology)
• Tubulin Modulators (pharmacology)
• Tumor Cells, Cultured