Abstract
Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms.
Highlights
Over the past decade, considerable research interest has been focused on developing innovative drugs able to target specific mechanisms strictly related to cancer initiation and progression
The synergism between bortezomib and HDAC inhibitors (HDACIs) is, due to the simultaneous inhibition of proteosome and aggresome, a dual block that determines intracellular accumulation of misfolded proteins and, as a consequence, cell apoptosis [31]. Another well described anticancer effect of HDACIs is the inhibition of angiogenesis, resulting from the downregulation of genes involved in angiogenesis, such as the vascular endothelial growth factor (VEGF) and the endothelial nitric oxide synthase [32,33,34]
Even if vorinostat demonstrated a low clinical activity in solid tumors, in consideration of its acceptable safety profile and the oral route of administration, further studies were carried out to investigate this drug in association with other antineoplastic agents in patients affected by different types of advanced solid tumors
Summary
Considerable research interest has been focused on developing innovative drugs able to target specific mechanisms strictly related to cancer initiation and progression. The major aim of this novel approach has been to produce anticancer agents with specific selectivity for cancer cells in order to obtain more effective treatments with less toxicities than classical approaches, such as chemotherapy and radiotherapy This has been made possible by the extraordinary progress in the understanding of molecular pathways involved in cancer development, including those regulating the cellular epigenome in hematological and solid tumor malignancies [1]. Epigenetics refers to the heritable changes in gene expression caused by complex mechanisms regulating histone modification and chromatin remodeling, DNA methylation, loss of imprinting, and microRNAs interference, without changes in the DNA nucleotide sequence [2,3] Dysregulation of these pathways has been related to the development of many different pathologies, including cellular aging and cancer [2,4]. New drug discovery programs using a wide range of procedures, including structure-based drug design and high-throughput screening, has allowed to identify multiple categories of HDAC inhibitors (HDACIs)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
