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

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Tumor Biology

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.

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Acknowledgments

This research was supported in part by grants from the National Natural Science Foundation of China

Author contributions

All authors carried out the experiments, participated in the design of the study and performed the statistical analysis, conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, China

    Huang Zhijun, Li Jianping & Li Dechun

  2. Department of Surgery, Yancheng First People’s Hospital, Yancheng, Jiangsu, China

    Huang Zhijun & Li Jianping

  3. Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China

    Wang Shusheng

  4. Department of Gastroenterology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China

    Min Han

  5. Department of Neurosurgery, The Sixth People’s Hospital of Yancheng, Yan-cheng, Jiangsu, China

    Qin Li-sen

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  1. Huang Zhijun
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  3. Min Han
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  4. Li Jianping
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Corresponding author

Correspondence to Li Dechun.

Ethics declarations

All animal procedures were performed according to the IACUC guidelines upon approval by all authors’ institutional review boards. All investigations were conducted according to the NIH regulations

Conflicts of interest

The authors declare that they have no competing interests.

Additional information

Huang Zhijun, Wang Shusheng and Min Han are co- first authors.

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Supplementary Figure 1

HCT-15, HCT-116 and DLD1 cells were pre-treated with MK-2206 (5 μM) or perifosine (5 μM) for 1 h, followed by 4SC-202 (1 μM) treatment for 72 h, cell survival was tested by MTT assay (a-c). Experiments were repeated four times in this figure, and similar results were obtained. Error bars indicate SD. *p < 0.05 vs. untreated control (“Ctrl”) group. # p < 0.05 vs. 4SC-202 only group (EPS 693 kb)

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Zhijun, H., Shusheng, W., Han, M. et al. Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells. Tumor Biol. 37, 10257–10267 (2016). https://doi.org/10.1007/s13277-016-4868-6

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  • DOI: https://doi.org/10.1007/s13277-016-4868-6

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