Combination of Valproic Acid and ATRA Restores RARβ2 Expression and Induces Differentiation in Cervical Cancer through the PI3K/Akt Pathway

Abstract

Epigenetic silencing of the tumor suppressor gene, RARβ2, through histone deacetylation has been established as an important process of cervical carcinogenesis. This pivotal role has led to the suggestion that a combination of retinoids selective for RARβ2 with histone deacetylase (HDAC) inhibitors may have therapeutic potential. Valproic acid (VPA), a HDAC inhibitor, has a critical role in the regulation of gene expression through histone acetylation and causes transformed cells to undergo growth arrest, differentiation, and apoptosis. Therefore, we hypothesized that the combination of VPA and ATRA could restore RARβ2 expression, thus resulting in enhanced anti-neoplastic activity in cervical cancer. Here, we show that VPA combined with ATRA led to hyperacetylation of histone H3 and a significant alteration of gene expression in cervical cancer cells, including RARβ2 gene expression, which was upregulated 50- to 90-fold. The combination therapy effectively inhibited the growth of cervical cancer cells more than the single agent treatment both in vitro and in vivo. The additive effects were associated with a significant upregulation of p21(CIP1) and p53 as well as a pronounced decrease in p-Stat3. Furthermore, the combined treatment led to cell cycle arrest predominantly at the G1 phase, and it preferentially induced cell differentiation rather than apoptosis in cervical cancer cells. The differentiation program was determined by the presence of E-cadherinmediated adhesion and activation of the PI3K/Akt pathway. Taken together, these results provide new insight into the mechanisms of enhanced antitumor activity of the HDAC inhibitor and ATRA regimen, thus offering a new therapeutic strategy for cervical cancer patients.

Targeting CD146 in combination with vorinostat for the treatment of ovarian cancer cells

“…The combination of vorinostat with AA98 attenuates Akt phosphorylation and 4E-BP1 expression. A similar association has been reported between Akt activation and HDACi sensitivity in cervical cancer cell lines (31). However, Akt kinase activity is not the sole determinant of sensitivity to vorinostat, and certain factors, such as S6K1, can result in sensitivity to vorinostat in the absence of Akt activation (32).…”

Emerging Biological Treatments for Uterine Cervical Carcinoma

“…Vorinostat , another histone deacetylase inhibitor, is under evaluation in respiratory papillomatosis, a disease related to HPV virus other than 16 and 18 97. Valproic acid (VPA) is a HDAC inhibitor tested, alone and in combination with retinoids or somatostatin receptor 2 cytotoxic conjugate agents, in preclinical studies of cervical HeLa cells 98,99. Preliminary results of a phase III randomized trial of hydralazine-valproate versus placebo added to cisplatin/topotecan showed advantages in PFS for epigenetic treatment 100.…”

Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer

“…And we found for the first time that PKM2 expression was closely related to the differentiation of tumor cells in ESCC. To further explore the association between PKM2 and the differentiation of tumor cells, we treated two ESCC cell lines with three different drugs, which could induce the differentiation of cancer cells . It was clearly observed that PKM2 expression gradually decreased with the extension of treatment in general.…”