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

Shaoyu Wu, Zhijian Guo, Chad D. Hopkins, Ning Wei, Edward Chu, Peter Wipf, John C. Schmitz

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The novel, chemically stabilized disorazole analog, (-)-CPM2-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 a-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.

Original languageEnglish (US)
Pages (from-to)40866-40879
Number of pages14
JournalOncotarget
Volume6
Issue number38
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Disorazole
  • Human colorectal cancer
  • Tubulin polymerization

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Bis-cyclopropane analog of disorazole C<sub>1</sub> is a microtubuledestabilizing agent active in ABCB1-overexpressing human colon cancer cells'. Together they form a unique fingerprint.

Cite this