TY - JOUR
T1 - Bis-cyclopropane analog of disorazole C1 is a microtubuledestabilizing agent active in ABCB1-overexpressing human colon cancer cells
AU - Wu, Shaoyu
AU - Guo, Zhijian
AU - Hopkins, Chad D.
AU - Wei, Ning
AU - Chu, Edward
AU - Wipf, Peter
AU - Schmitz, John C.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Disorazole
KW - Human colorectal cancer
KW - Tubulin polymerization
UR - http://www.scopus.com/inward/record.url?scp=84950969741&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84950969741&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.5885
DO - 10.18632/oncotarget.5885
M3 - Article
C2 - 26506423
AN - SCOPUS:84950969741
SN - 1949-2553
VL - 6
SP - 40866
EP - 40879
JO - Oncotarget
JF - Oncotarget
IS - 38
ER -