Kinetics of Selective HDAC6 Inhibitors (HDAC6i) and their Biological Effect on Cancer Cells and Macrophages
Open AccessHistone deacetylase 6 (HDAC6) is involved in many physiological processes, including cell motility and metastasis, cell signaling, protein folding and degradation, and inflammation, making HDAC6 a target for the treatment of several diseases. Aberrant expressions of HDAC6 have been reported in several types of cancer, including ovarian cancer, malignant melanoma, and breast cancer. HDAC6 functions mainly as a tubulin deacetylase enzyme and its activity has been regulated by developing several selective drugs known as histone deacetylase 6 inhibitors (HDAC6i). Briefly, increasing tubulin acetylation via specific HDAC6 inhibition has shown protective effects in many diseases such as cancers, neurological disorders, and heart and lung diseases. On tumor cells, HDAC6i have been found to induce apoptosis and differentiation and inhibit cellular growth and angiogenesis. Moreover, evidence suggests that HDAC6 plays an essential role in regulating inflammatory and immune responses such as macrophages responses. This thesis work determined the kinetics of selected HDAC6is and suggests that studying the kinetic inhibition properties of HDAC6i and how this affects cell function is critical to establish their therapeutic efficacy. Likewise, evaluating HDAC6 inhibitor properties using α-tubulin acetylation is not predictive of their function on cellular activity on macrophages. To illustrate, macrophages treated with the HDAC6 inhibitor Nexturastat and HDAC6 (11352) experienced an increase in the activation of M1 macrophages. However, tubacin and SP-2-225 did not provoke a significant change in the polarization of macrophages.
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