<p>HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice</p>

Abstract

Background: Hepatocellular carcinoma (HCC) is a frequently diagnosed cancer and a leading cause of cancer-related death worldwide. Its rapid progression, combined with the limited treatment options at late stages, imposes the need for early detection and aggressive intervention. Based on the knowledge that hepatocarcinogenesis is significantly influenced by histone acetylation, we directed our search for novel HCC therapeutics among histone deacetylation inhibitors (HDACi). The aim of the present study was to investigate the effect of HDAC1/2 inhibitor Romidepsin in the well-established mouse model of diethylnitrosamine (DEN)-induced HCC. Materials and Methods: C56BL/6 mice were treated with Romidepsin at the critical point of 10 months after DEN challenge and their livers were examined 2 months later using histopathology and morphometry. Protein levels were assessed in serum using ELISA and in liver tissues using Western blot and immunohistochemistry (in-situ detection). Gene expression was quantified using real-time PCR. Results: Romidepsin suppressed cancer progression. This effect was associated with decreased proliferation and increased apoptosis of cancer cells. The cell cycle regulator CK2a, the anti-inflammatory molecule PPAR-γ, and the tumor suppressors PTEN and CYLD were upregulated in treated HCC. By contrast, the expression of PI3K, NF-κB p65 and c-Jun was reduced. In line with this result, the levels of two major apoptosis regulators, ie, BAD and the multifunctional protein c-Met, were lower in the blood serum of treated mice compared to the untreated mice with HCC. Conclusion: These findings suggest that Romidepsin, a drug currently used in the treatment of lymphoma, could also be considered in the management of early-stage HCC.

Chalcone Derivative B8HA as A Novel Histone Deacetylase and Tubulin Dual Inhibitors, Inhibits Triple-Negative Breast Cancer Cells Proliferation

“…It was identi ed that the treatment of B8HA was accompanied by a reduction in cell proliferation, as indicated by lower numbers of Ki-67-positive cells. This nding is in accordance with a recent study, in which HDAC1/2 inhibitor Romidepsin-mediated Ki-67 expression suppression in hepatocellular carcinoma mice was reported 32 . In addition, previous studies had shown that HDACi MS-275 and SAHA all downregulated the expression of MMP-2 in MDA-MB-468 tumor tissues as well as inhibited the lung metastasis 33 .…”

Deacetylation of Transcription Factors in Carcinogenesis

“…In conclusion, romidepsin suppresses the early stage of HCC. The suggested mechanism could be associated with the tumor-suppression activity of romidepsin through the deregulation of critical cancer-related proteins, including NF-κB [93]. In line with these observations, the subsequent finding indicates that the activation of the NF-κB signaling pathway is observed in Kaposi's sarcoma (KS), an endothelial spindle-shaped cell tumor induced by KS-associated herpesvirus (KSHV), when HDAC1 is downregulated.…”

Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio

“…However, Schaefer et al, demonstrated that PPARγ is overexpressed in neoplastic lesions [ 24 ]. Recently, Afaloniati et al, confirmed in a HCC murine model, that treatment with romidepsin, an HDACs inhibitor, can modulate the translocation of PPARγ to the nucleus, proposing this transcriptional factor as a possible anti-inflammatory mediator [ 25 ]. Our analysis in normal human liver showed that there is a basal nuclear expression of PPARγ, while in human HCC tissue exists and cytoplasmic PPARγ overexpression.…”