Dual inhibition of histone deacetylases and phosphoinositide 3-kinases: effects on Burkitt lymphoma cell growth and migration

Abstract

Burkitt lymphoma is a highly aggressive non-Hodgkin lymphoma that is characterized by MYC deregulation. Recently, the PI3K pathway has emerged as a cooperative prosurvival mechanism in Burkitt lymphoma. Despite the highly successful results of treatment that use high-dose chemotherapy regimens in pediatric Burkitt lymphoma patients, the survival rate of pediatric patients with progressive or recurrent disease is low. PI3Ks are also known to regulate cell migration, and abnormal cell migration may contribute to cancer progression and dissemination in Burkitt lymphoma. Little is known about Burkitt lymphoma cell migration, but the cooperation between MYC and PI3K in Burkitt lymphoma pathogenesis suggests that a drug combination could be used to target the different steps involved in Burkitt lymphoma cell dissemination and disease progression. The aim of this study was to investigate the effects of the histone deacetylase inhibitor suberoylanilide hydroxamic acid combined with the PI3K inhibitor LY294002 on Burkitt lymphoma cell growth and migration. The combination enhanced the cell growth inhibition and cell-cycle arrest induced by the PI3K inhibitor or histone deacetylase inhibitor individually. Moreover, histone deacetylase inhibitor/PI3K inhibitor cotreatment suppressed Burkitt lymphoma cell migration and decreased cell polarization, Akt and ERK1/2 phosphorylation, and leads to RhoB induction. In summary, the histone deacetylase inhibitor/PI3Ki combination inhibits cell proliferation and migration via alterations in PI3K signaling and histone deacetylase activity, which is involved in the acetylation of α-tubulin and the regulation of RhoB expression.

Therapeutic Potential of CUDC-907 (Fimepinostat) for Hepatocarcinoma Treatment Revealed by Tumor Spheroids-Based Drug Screening

“…Previous reports have shown that CUDC-907 is a dualacting inhibitor of PI3K and HDAC, and exhibits predominant anticancer effects in c-Myc-driven tumors (Ferreira et al, 2016;Sun et al, 2017b). The c-Myc oncoprotein is an essential transcription factor that regulates the expression of many genes involved in cell growth, proliferation, and metabolic pathways (Farrell and Sears, 2014).…”

CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression

“…c-Myc is a member of the MYC family, and its overexpression is positively correlated with the degree of tumor malignancy; thus inhibiting c-Myc protein may benefit PDAC treatment. CUDC-907, a dual-acting inhibitor of PI3K and HDAC, exhibits predominant anticancer effects in c-Myc-driven tumors, such as diffuse large B cell lymphoma [16,18,19], indicating that this drug may be an effective therapy across a wide range of hematologic and solid cancers known to be dependent on c-Myc. This study demonstrated CUDC-907-induced growth inhibition of a panel of human pancreatic cancer cell lines, indicating the potent antiproliferative activity of CUDC-907 in vitro.…”

“…CUDC-907 was first reported by the Rudi Bao group in 2012, and it is a novel dual-acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC) [15]. As a single small compound, CUDC-907 has significant potential against cancer growth and metastasis through the simultaneous disruption of multiple oncogenic signaling networks [15][16][17][18][19]. Apart from suppressing AKT activation and accumulation of histone acetylation (direct targets of PI3K and HDAC, respectively), changes in c-Myc level is one of the most vital changes after treatment.…”

The RhoB small GTPase in physiology and disease

“… 71,72 In addition, combined inhibition of HDACs and phosphoinositide 3-kinases (PI3Ks) in Burkitt lymphoma cells increases RhoB expression, correlating with reduced cell proliferation and migration. 73 Interestingly, RhoB contributes to either cell cycle arrest or apoptosis depending on which HDAC isoform is inhibited, 74 suggesting that RhoB may act together with other HDAC isoform-selective targets to affect cellular responses. On the other hand RhoB expression is reduced by several oncogenes including Ras, EGFR or Akt.…”