Valproic acid exhibits anti-tumor activity selectively against EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer via induction of ErbB family members-targeting microRNAs

Abstract

Background Deregulated ErbB signaling plays an important role in tumorigenesis of pancreatic cancer. However, patients with pancreatic cancer benefit little from current existed therapies targeting the ErbB signaling. Here, we explore the potential anti-tumor activity of Valproic acid against pancreatic cancer via targeting ErbB family members. Methods Cell viability assay and apoptosis evaluation were carried out to determine the efficacy of VPA on pancreatic cancer cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone associated DNA fragments. Lentiviral expression system was used to introduce overexpression of exogeneous genes or gene-targeting short hairpin RNAs (shRNAs). qRT-PCR was carried out to analyze the mRNAs and miRNAs expression levels. Tumor xenograft model was established to evaluate the in vivo anti-pancreatic cancer activity of VPA. Results VPA preferentially inhibited cell proliferation/survival of, and induced apoptosis in EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer cells within its clinically achievable range [40~100 mg/L (0.24~0.6 mmol/L)]. Mechanistic investigations revealed that VPA treatment resulted in simultaneous significant down-regulation of EGFR, ErbB2, and ErbB3 in pancreatic cancer cells likely via induction of ErbB family members-targeting microRNAs. Moreover, the anti-pancreatic cancer activity of VPA was further validated in tumor xenograft model. Conclusions Our data strongly suggest that VPA may be added to the treatment regimens for pancreatic cancer patients with co-overexpression of the ErbB family members. Electronic supplementary material The online version of this article (10.1186/s13046-019-1160-9) contains supplementary material, which is available to authorized users.

Similar Population of CD133+ and DDX4+ VSEL-Like Stem Cells Sorted from Human Embryonic Stem Cell, Ovarian, and Ovarian Cancer Ascites Cell Cultures: The Real Embryonic Stem Cells?

“…Some other studies showed that valproic acid, a fatty acid derivative, was efficient in ex vivo expansion of other types of stem cells, such as haematopoietic stem cells from umbilical cord blood [54] and placenta-derived mesenchymal/stromal stem cells [55]. Otherwise, it is an important FDA-approved drug component with several beneficial effects and of great interest for the treatment of different types of cancers [56]. As a medication, it is mostly used to treat seizure disorders, mental/mood conditions, such as manic phase of bipolar disorder [57], and to prevent migraine headaches [58].…”

Sparse Graph Regularization Non-Negative Matrix Factorization Based on Huber Loss Model for Cancer Data Analysis

“…ERBB2, commonly referred to as HER2, may be critical for enhancing the synergistic effect of PI3K inhibitors in HNSC patients (Michmerhuizen et al, 2019). It is generally believed that dysregulated ERBB2 signaling plays a key role in the development of pancreatic cancer (Lin et al, 2019). For the treatment of intestinal adenocarcinoma, ERBB2 mutations and amplification in small intestinal adenocarcinoma patients also make a great contribution (Adam et al, 2019).…”

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

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“…discovered that brivaracetam and lacosamide regulate the expression of miRNAs in glioma cells; in particular, the regulation of miR-195-5p seems to affect the cell cycle, while the regulation of miR-107 seems to be involved in the inhibition of cell migration; therefore, these two drugs also have the potential to be an adjuvant treatment for glioma [ 71 ]. A recent study demonstrated that the VPA-induced simultaneous downregulation of EGFR, ErbB2, and ErbB3 in pancreatic cancer cells could slow the progression of pancreatic cancer, which was mainly attributed to the induction of ErbB family member-targeting miRNAs [ 40 ]. Moreover, recent evidence has shown that miR-145-5p upregulation in thymoma cells mediated by VPA exhibits antitumour effects as well as better responsiveness to chemotherapy [ 72 ].…”