Histone deacetylase‐based dual targeted inhibition in multiple myeloma

Abstract

Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC‐based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual‐inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting‐point for both reducing therapeutic doses and lowering the risk of developing drug resistance.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

“…Also, the simultaneous inhibition of Class I phosphoinositide 3-kinases (PI3K) and HDAC has shown promise for treating various cancers [261]. Several PI3K/HDAC dual inhibitors have been disclosed, showing promising anticancer properties [262][263][264][265].…”

Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine‐induced killer cell efficiency in multiple myeloma via the NKG2D pathway

“… 17 Nevertheless, the results of several preclinical evaluations with HDACis, including combination therapies in MM, suggest that they may be an interesting alternative to the established regimen. 3 , 18 The scenario is quite similar in case of CIK cell immunotherapy in the clinic, 10 which recently turned 30 years old and already has a history of successful clinical trials in MM. Surprisingly, HDACis have never been tested in combination with CIK cells in the clinical trials.…”

“… 1 , 2 Of particular interest in MM are variable patterns of histone deacetylase (HDACs), which have led to the exploration of several histone deacetylase inhibitors (HDACis)‐based interventions in vitro , in vivo and in clinical trials over the last decades. 3 , 4 , 5 …”

Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells

“…Myeloma cells often have high levels of histone deacetylases (HDACs), which causes the chromatin to become tightly packed. This leads to the suppression of genes that play a role in apoptosis and cell cycle regulation [ 130 , 135 ]. The process of epigenetic suppression has a role in the resistance of myeloma cells to both chemotherapeutic drugs and targeted therapy.…”

“…The process of epigenetic suppression has a role in the resistance of myeloma cells to both chemotherapeutic drugs and targeted therapy. HDAC inhibitors have demonstrated potential in correcting these epigenetic alterations, reinstating the expression of crucial genes, and enhancing the susceptibility of myeloma cells to treatment [ 130 , 135 , 136 ].…”