2. Academic Validation
  3. Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells

Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells

  • Tumour Biol. 2016 Aug;37(8):10257-67. doi: 10.1007/s13277-016-4868-6.
Huang Zhijun 1 2,  Wang Shusheng 3,  Min Han 4,  Li Jianping 1 2,  Qin Li-Sen 5,  Li Dechun 6
Affiliations

Affiliations

  • 1 Department of Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People's Republic of China.
  • 2 Department of Surgery, Yancheng First People's Hospital, Yancheng, Jiangsu, People's Republic of China.
  • 3 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China.
  • 4 Department of Gastroenterology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China.
  • 5 Department of Neurosurgery, The Sixth People's Hospital of Yancheng, Yan-cheng, Jiangsu, People's Republic of China.
  • 6 Department of Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People's Republic of China. [email protected].
PMID: 26831668 DOI: 10.1007/s13277-016-4868-6
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.

Keywords

4SC-202; AKT; Chemo-sensitization and pre-clinical studies; Colorectal cancer (CRC); Histone deacetylase (HDAC).

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