| First Author | Bond MJ | Year | 2018 |
| Journal | Mol Cancer Res | Volume | 16 |
| Issue | 9 | Pages | 1361-1372 |
| PubMed ID | 29769406 | Mgi Jnum | J:265656 |
| Mgi Id | MGI:6199246 | Doi | 10.1158/1541-7786.MCR-18-0178 |
| Citation | Bond MJ, et al. (2018) Spindle Assembly Disruption and Cancer Cell Apoptosis with a CLTC-Binding Compound. Mol Cancer Res 16(9):1361-1372 |
| abstractText | AK3 compounds are mitotic arrest agents that induce high levels of gammaH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC50 of approximately 50 nmol/L. AK306 was active on a broad spectrum of cancer cell lines with total growth inhibition values ranging from approximately 25 nmol/L to 25 mumol/L. Using biotin and BODIPY-linked derivatives of AK306, binding to clathrin heavy chain (CLTC/CHC) was observed, a protein with roles in endocytosis and mitosis. AK306 inhibited mitosis and endocytosis, while disrupting CHC cellular localization. Cells arrested in mitosis by AK306 showed the formation of multiple microtubule-organizing centers consisting of pericentrin, gamma-tubulin, and Aurora A foci, without apparent centrosome amplification. Cells released from AK306 arrest were unable to form bipolar spindles, unlike nocodazole-released cells that reformed spindles and completed division. Like AK306, CHC siRNA knockdown disrupted spindle formation and activated p53. A short-term (3-day) treatment of tumor-bearing APC-mutant mice with AK306 increased apoptosis in tumors, but not normal mucosa. These findings indicate that targeting the mitotic CHC complex can selectively induce apoptosis and may have therapeutic value.Implication: Disruption of clathrin with a small-molecule inhibitor, AK306, selectively induces apoptosis in cancer cells by disrupting bipolar spindle formation. Mol Cancer Res; 16(9); 1361-72. (c)2018 AACR. |
