A novel strategy to block mitotic progression for targeted therapy

Abstract

Background: Blockade of mitotic progression is an ideal approach to induce mitotic catastrophe that suppresses cancer cell expansion. Cdc20 is a critical mitotic factor governing anaphase initiation and the exit from mitosis through recruiting substrates to APC/C for degradation. Results from recent TCGA (The Cancer Genome Atlas) and pathological studies have demonstrated a pivotal oncogenic role for Cdc20-APC/C in tumor progression as well as drug resistance. Thus, deprivation of the mitotic role for Cdc20-APC/C by either inhibition of Cdc20-APC/C activity or elimination of Cdc20 protein via induced protein degradation emerges as an effective therapeutic strategy to control cancer. Methods: We designed a proteolysis targeting chimera, called CP5V, which comprises a Cdc20 ligand and VHL binding moiety bridged by a PEG5 linker that induces Cdc20 degradation. We characterized the effect of CP5V in destroying Cdc20, arresting mitosis, and inhibiting tumor progression by measuring protein degradation, 3D structure dynamics, cell cycle control, tumor cell killing and tumor inhibition using human breast cancer xenograft mouse model. Findings: Results from our study demonstrate that CP5V can specifically degrade Cdc20 by linking Cdc20 to the VHL/VBC complex for ubiquitination followed by proteasomal degradation. Induced degradation of Cdc20 by CP5V leads to significant inhibition of breast cancer cell proliferation and resensitization of Taxol-resistant cell lines. Results based on a human breast cancer xenograft mouse model show a significant role for CP5V in suppressing breast tumor progression. Interpretation: CP5V-mediated degradation of Cdc20 could be an effective therapeutic strategy for antimitotic therapy.

Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

“…Our results are consistent with previous RNAi-based experiments demonstrating that Cdc20 must be reduced to less than 5% of normal levels to significantly delay mitotic exit 31 . The ability of a recently-reported apcin-based proTAC to induce mitotic arrest and cell death may thus arise from its ability to both reduce Cdc20 levels and antagonize Cdc20 function 40 . Furthermore, reducing APC/C Cdc20 activity with proTAME also strongly sensitizes cells to the ability of apcin to block mitotic exit 15 .…”

Cancer Stem Cell Characteristics by Network Analysis of Transcriptome Data Stemness Indices in Breast Carcinoma

“…Gong et al showed that the overexpression of NCAPG could promote HCC cell proliferation and reduce HCC cell apoptosis [ 24 ]. Studies have reported that Cdc20 is a pivotal mitotic factor governing anaphase initiation, and Cdc20-APC/C is fast becoming highlighted as a key instrument in tumor progression [ 25 ]. Evidence has shown that CDC20 , a significant cell division regulator, exhibits an oncogenic function and plays vital roles in tumorigenesis and progression of solid tumors [ 26 ].…”

Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

“…Currently, apoptosis tolerance-mediated MDR has been considered the most common and complex drug-resistant mechanism [5,33] . However, in addition to apoptosis, anticancer drugs can also trigger other anticancer mechanisms, such as autophagy, MC, ferroptosis, pyroptosis, necrosis and senescence, to inhibit the proliferation of cancer cells and kill them by avoiding the apoptosis-resistant pathway [11,17,34,35] . In our previous studies, we con rmed that BZML has potent anticancer activity and overcomes MDR by inducing MC in A549/Taxol cells, an MDR cell line [24] .…”

“…Importantly, a growing body of literature shows that apoptosis is not the sole anticancer mechanism and that the activation of nonapoptotic cell death is a promising strategy for overcoming MDR [8,9] . Mitotic catastrophe (MC) is a newly identi ed type of anticancer mechanism in cancer treatment and MDR prevention and has received more attention in recent years [10,11] . Additionally, a number of studies have shown that MC and senescence are closely related and that cancer cell death by MC is often accompanied by a senescence-like phenotype [12][13][14] .…”