title: Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells.
abstract: Histone deacetylase (HDAC) overactivity in colorectal cancer (CRC) promotes cancer progression. In the current study, we showed that 4SC-202, a novel class I HDAC inhibitor (HDACi), potently inhibited survival and proliferation of primary human colon cancer cells and established CRC lines (HT-29, HCT-116, HT-15, and DLD-1). Yet, the same 4SC-202 treatment was non-cytotoxic to colon epithelial cells where HDAC-1/-2 expressions were extremely low. 4SC-202 provoked apoptosis activation in CRC cells, while caspase inhibitors (z-VAD-CHO and z-DVED-CHO) significantly alleviated 4SC-202-exerted cytotoxicity in CRC cells. Meanwhile, 4SC-202 induced dramatic G2-M arrest in CRC cells. Further studies showed that AKT activation might be an important resistance factor of 4SC-202. 4SC-202-induced cytotoxicity was dramatically potentiated with serum starvation, AKT inhibition (by perifosine or MK-2206), or AKT1-shRNA knockdown in CRC cells. On the other hand, exogenous expression of constitutively active AKT1 (CA-AKT1) decreased the sensitivity by 4SC-202 in HT-29 cells. Notably, 4SC-202, at a low concentration, enhanced oxaliplatin-induced in vitro anti-CRC activity. In vivo, we showed that oral gavage of 4SC-202 inhibited HT-29 xenograft growth in nude mice, and when combined with oxaliplatin, its activity was further strengthened. Together, these pre-clinical results indicate that 4SC-202 may be further investigated as a valuable anti-CRC agent/chemo-adjuvant.
authors.affiliation: Department of Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People's Republic of China.|Department of Surgery, Yancheng First People's Hospital, Yancheng, Jiangsu, People's Republic of China.
authors.forename: Huang
authors.initials: H
authors.lastname: Zhijun
authors.affiliation: Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Shusheng
authors.affiliation: Department of Gastroenterology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People's Republic of China.|Department of Surgery, Yancheng First People's Hospital, Yancheng, Jiangsu, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Jianping
authors.affiliation: Department of Neurosurgery, The Sixth People's Hospital of Yancheng, Yan-cheng, Jiangsu, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li-Sen
authors.affiliation: Department of Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People's Republic of China. drlidechunsuda@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Dechun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; C000614036:domatinostat
keywords: 4SC-202; AKT; Chemo-sensitization and pre-clinical studies; Colorectal cancer (CRC); Histone deacetylase (HDAC)
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