Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

Li, Xiaofei; Zhu, Yanshuang; He, Hongbin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

doi:10.1016/j.bbrc.2013.05.088

Cited by 26 publications

(24 citation statements)

References 26 publications

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“…However, the HDAC inhibitory mechanism of VPA is relatively well known. [8][9][10] HDAC is reported to be aberrantly expressed in diverse cancers. HDAC inhibition can increase the expression of several genes by accelerating their transcription, which can enhance the innate immune system and lead to suppression of tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…HDAC inhibition can increase the expression of several genes by accelerating their transcription, which can enhance the innate immune system and lead to suppression of tumor growth. 9,17 VPA alters the expression of various genes involved in the interaction with the cellular immune system, which is known Figure 5. Generation of mouse CIK cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, a synergistic effect of VPA with other agents has been reported in some promising results. [8][9][10] VPA upregulates MIC-A and MIC-B, 11 and this upregulation on the tumor surface enhances CIK cells effects. Moreover, VPA has been safely used as an antiepileptic drug for decades, it is relatively inexpensive, and its adverse effects have been regarded as tolerable.…”

Section: Introductionmentioning

confidence: 98%

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Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

Lee

Nam

Chang

et al. 2017

Cancer Biology & Therapy

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Objective: Long-term prognosis of hepatocellular carcinoma (HCC) remains poor owing to the lack of treatment options for advanced HCC. Cytokine-induced killer (CIK) cells are ex vivo expanded T lymphocytes expressing both NK-and T-cell markers. CIK cell therapy alone is insufficient for treating advanced HCC. Thus, this study aimed to determine whether treatment with CIK cells combined with valproic acid (VPA) could provide a synergistic effect to inhibit tumor growth in a mouse model of HCC. Methods: Upregulation of natural killer group 2D (NKG2D) ligands (retinoic acid early inducible 1 [RAE-1], mouse; major histocompatibility complex class I polypeptide-related sequence A [MIC-A], human) were evaluated by FACS. VPA concentrations that did not reduce tumor volume were calculated to avoid VPA cytotoxicity in a C3H mouse model of HCC. CIK cells were generated from mouse splenocytes using interferon gamma, a CD3 monoclonal antibody, and interleukin 2. The potential synergistic effect of CIK cells combined with VPA was evaluated in the mouse model and tissue pathology was investigated. Results: After 40 h of incubation with VPA, RAE-1 and MIC-A expression were increased in 4 HCC cell lines compared with that in control (2.3-fold in MH-134, 2.4-fold in Huh-7, 3.7-fold in SNU-761, and 6.5-fold in SNU-475). The maximal in vivo VPA dosage that showed no significant cytotoxicity compared with control was 10 mg/kg/day. CIK cells were well generated from C3H mouse splenocytes. After 7 d of treatment with CIK cells plus VPA, a synergistic effect was observed on relative tumor volume in the mouse model of HCC. While the relative tumor volume in untreated control mice increased to 11.25, that in the combination treatment group increased to only 5.20 (P D 0.047). Conclusions: The VPA-induced increase in NKG2D ligands expression significantly enhanced the effects of CIK cell therapy in a mouse model of HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

Lee

Nam

Chang

et al. 2017

Cancer Biology & Therapy

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“…Moreover, VPA was reported to sensitize anaplastic thyroid carcinoma (ATC) cells to DOX, which caused apoptosis via the induction of histone hyperacetylation or apoptosis-related gene expression [30][31][32]. Concurrently, several studies demonstrated that VPA showed synergistic effects with well-known anticancer drugs, such as aspirin, flavopiridol, mitomycin C, cisplatin, adriamycin, and DOX, and could induce cell death in various cancer cells [19,30,33,34]. The synergistic anticancer effect of VPA with other drugs was primarily considered to occur through histone acetylation and alteration of apoptosis related gene expression, but the underlying mechanisms of the synergistic effect and drug internalization into the cell remain unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it has been used as an anticonvulsant and a mood-stabilizing drug, similar to lithium, and also has neuroprotective effects in neurodegenerative conditions [9][10][11][12]. VPA was recognized as a hepatotoxic drug [13,14]; additionally, several studies have demonstrated that VPA treatment led to growth inhibition or apoptosis or both in a range of cancer cells [15][16][17][18], including HCC cells [19][20][21].…”

Section: Of 15mentioning

confidence: 99%

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Anti-Proliferation Effects in Hepatocellular Carcinoma Cells

Saha¹,

Yin²,

Kim³

et al. 2017

Preprint

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Abstract:We evaluated the mono-and combination-therapy effects of valproic acid (VPA) and doxorubicin (DOX) in hepatocellular carcinoma (HCC) and identified a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.

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Histone deacetylase inhibitors (HDACi), the ongoing epigenetic agents to enhance chemotherapy sensitization

Sun

Song

Sun

et al. 2021

Epigenetic Regulation in Overcoming Chemoresistance

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Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

Cited by 26 publications

References 26 publications

Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Anti-Proliferation Effects in Hepatocellular Carcinoma Cells

Histone deacetylase inhibitors (HDACi), the ongoing epigenetic agents to enhance chemotherapy sensitization

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