Use of Small Chemical Vacuolin-1 as a Novel Anti-Cancer Therapeutic Drug
- Jianbo YUE (Principal Investigator / Project Coordinator)Department of Biomedical Sciences
- Siu Kie Joseph AU (Co-Investigator)
- Yingying LU (Co-Investigator)Department of Biomedical Sciences
- M YANG (Co-Investigator)Department of Biomedical Sciences
- Tak-Chun Timothy YIP (Co-Investigator)
DescriptionTumour cells normally exhibit extremely high basal autophagic activity and are more sensitive to autophagy inhibitors than normal cells. Currently, over 30 preclinical or clinical trials on anti-cancer ability of chloroquine (CQ), an autophagy inhibitor, are ongoing. Yet, majority of the autophagy inhibitors, like CQ, lack specificity, or potency, or both. To search for potent and specific autophagy modulators, we developed a high throughput fluorescence imaging-based assay to screen compounds affecting autophagy in HeLa cells. We found that the small chemical vacuolin-1 potently and reversibly inhibits autophagy progression by activating RAB5A. Vacuolin-1 treatment also results in a defect in general endosomal-lysosomal degradation. Amazingly, vacuolin-1 is much less toxic but at least 10 folds more potent in inhibiting autophagy compared to CQ. Several vacuolin-1 analogues with similar potency have also been identified by virtual drug screening. Vacuolin-1 and its analogues present a novel class of drug that can potently and reversibly modulate autophagy and endocytosis. As expected, vacuolin-1 markedly inhibits the colony formation and migration of tumour cells in vitro. Preliminary study further showed that vacuolin-1 significantly inhibits tumour progression in xenograft mouse model but showed little acute toxicity in mice. Hence the objective of this project is to use vacuolin-1 alone or in combination with chemotherapeutic drugs to inhibit tumour progression and metastasis in xenograft mouse models and to assess their toxicity. It is expected that vacuolin-1 and its analogues should provide a novel therapeutic strategy for fighting cancers.
|Effective start/end date||1/09/15 → 31/05/17|