Rationale behind using valproic acid for Non-Hodgkin lymphoma: a biomolecular perspective

H. Ridwansyah, I. Wijaya, M.H. Bashari, A.H.S. Kartamihardja, B.S. Hernowo

Graduate School of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. ridwansyah19001@mail.unpad.ac.id

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• Hematology
• Pharmacology

OBJECTIVE: Non-Hodgkin lymphoma (NHL) is a hematological malignancy with a high rate of relapse and refractory cases. It is believed to be caused by resistance to standard treatment modalities. Valproic acid (VPA), previously used as a broad-spectrum anticonvulsant drug, has been proposed for NHL owing to its action of epigenetic modification by inhibiting histone deacetylase. However, VPA studies on NHL are limited. This review describes the rationale behind the use of VPA for NHL treatment, particularly focusing on its molecular mechanism of action.

MATERIALS AND METHODS: This is a narrative review. The literature search strategy for indexed Scopus articles was performed randomly using PubMed and MEDLINE as the primary sources. No specific term was used.

RESULTS: Several mechanisms are responsible for NHL development. VPA can modulate these mechanisms via epigenetic and nonepigenetic modifications. It may also have an impact on the proteins responsible for treatment resistance. The mechanisms of action of VPA in NHL are as follows: the induction of cell cycle arrest via the upregulation of cyclin-dependent protein kinase inhibitors; induction of Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis; inactivation of B-cell lymphoma 6; inhibition of Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt, and nuclear factor kappa B signaling pathways; upregulation of tumor antigen as the primary target of immunotherapy; and strengthening of tumor immunosurveillance.

CONCLUSIONS: Based on its biomolecular mechanism of action, VPA appears to be a promising initial treatment before initiating the standard treatment in patients with NHL to overcome resistance.

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