Journal
MOLECULAR CANCER THERAPEUTICS
Volume 17, Issue 4, Pages 763-775Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-0332
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [U1402222, 81703344]
- Guangdong Innovative Research Team Program [2011Y073]
Ask authors/readers for more resources
Our previous study reported that SKLB-23bb, an orally bioavailable HDAC6-selective inhibitor, exhibited superior antitumor efficiency both in vitro and in vivo in comparison with ACY1215, a HDAC6-selective inhibitor recently in phase II clinical trial. This study focused on the mechanism related to the activity of SKLB-23bb. We discovered that despite having HDAC6-selective inhibition equal to ACY1215, SKLB-23bb showed cytotoxic effects against a panel of solid and hematologic tumor cell lines at the low submicromolar level. Interestingly, in contrast to the reported HDAC6-selective inhibitors, SKLB-23bb was more efficient against solid tumor cells. Utilizing HDAC6 stably knockout cell lines constructed by CRISPR-Cas9 gene editing, we illustrated that SKLB-23bb could remain cytotoxic independent of HDAC6 status. Investigation of the mechanism confirmed that SKLB-23bb exerted its cytotoxic activity by additionally targeting microtubules. SKLB-23bb could bind to the colchicine site in beta-tubulin and act as a microtubule polymerization inhibitor. Consistent with its microtubule-disrupting ability, SKLB-23bb also blocked tumor cell cycle at G(2)-M phase and triggered cellular apoptosis. In solid tumor xenografts, oral administration of SKLB-23bb efficiently inhibited tumor growth. These results suggested that SKLB-23bb was an orally bioavailable HDAC6 and microtubule dual targeting agent. The microtubule targeting profile enhanced the antitumor activity and expanded the antitumor spectrum of SKLB-23bb, thus breaking through the limitation of HDAC6 inhibitors. (C) 2018 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available