Virtual Library
Start Your Search
S. Sun
Author of
-
+
MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
-
+
MINI14.10 - CAY10603, a Novel Inhibitor of HDAC6, Suppresses Non-Small Cell Lung Cancer Cell Growth via Modulating Both Autophagy and Apoptosis Pathways (ID 1305)
11:40 - 11:45 | Author(s): S. Sun
- Abstract
Background:
Histone deacetylase 6 (HDAC6) is a key regulator of many signaling pathways linked to cancer. But unlike other HDACs, inhibition of HDAC6 is believed not to be associated with severe toxicity, making HDAC6 a possible cancer treatment target. Overexpression of HDAC6 has been observed in many types of cancer including NSCLC. Knockdown of HDAC6 sensitizes NSCLC cell lines to chemotherapy induced cell apoptosis. Apoptosis and autophagy are the 2 cellular processes likely to alter efficacy of a therapeutic agent. Autophagy confers resistance to chemotherapy by inhibiting apoptosis. HDAC6 controls autophagosome maturation and is essential for autophagy. CAY10603 is a potent and selective inhibitor of HDAC6. Therefore, inhibition of HDAC6 by CAY10603 could be a promising strategy to treat NSCLC by targeting both apoptosis and autophagy pathways.
Methods:
We evaluated the effect of CAY10603 alone or in combination with autophagy inhibition on cell proliferation, apoptosis and autophagy in two human NSCLC cell lines, A549 and H460. Pharmacological (chloroquine or bafilomycin-A1) or genetic (knockdown of ATG5 or Beclin1 with shRNA) approaches were utilized to block autophagy. Cell proliferation of untreated or drug-treated cells was measured by CCK8 assay. Percentage of apoptotic cells was measured using PE-conjugated Annexin V with a flow cytometer. Autophagy was determined by conversion of LC3I to LC3II and p62 degradation using Western blot.
Results:
CAY10603 inhibits NSCLC cell proliferation and induces apoptosis. CAY10603 also inhibits HDAC6 dependent basal autophagy and activates the PI3K-Akt-mTOR pathway. Meanwhile, HDAC6 independent autophagy exists in NSCLC cells and confers resistance to CAY10603. Cotreatment with chloroquine or bafilomycin-A1 promotes the autophagy inhibition, cell growth suppression and apoptosis induction of NSCLC cells compared to CAY10603 alone. Knockdown of ATG5 or Beclin1 by shRNA also increased CAY10603-induced cytotoxicity in above NSCLC cells.
Conclusion:
Our results indicate that CAY10603 may be a promising agent for the treatment of NSCLC by modulating autophagy and apoptosis pathways. Furthermore, the combination of CAY10603 with classical autophagy inhibitors represents a promising therapeutic strategy that warrants further clinical evaluation in NSCLC.
