A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth

Abstract

Background:This study investigates whether a histone deacetylase subtype 6 (HDAC6) inhibitor could be used in the treatment of solid tumours.Methods:We evaluated the effect of a novel inhibitor, C1A, on HDAC6 biochemical activity and cell growth. We further examined potential of early noninvasive imaging of cell proliferation by [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) to detect therapy response.Results:C1A induced sustained acetylation of HDAC6 substrates, α-tubulin and HSP90, compared with current clinically approved HDAC inhibitor SAHA. C1A induced apoptosis and inhibited proliferation of a panel of human tumour cell lines from different origins in the low micromolar range. Systemic administration of the drug inhibited the growth of colon tumours in vivo by 78%. The drug showed restricted activity on gene expression with <0.065% of genes modulated during 24 h of treatment. C1A treatment reduced tumour [18F]FLT uptake by 1.7-fold at 48 h, suggesting that molecular imaging could provide value in future studies of this compound.Conclusion:C1A preferentially inhibits HDAC6 and modulates HDAC6 downstream targets leading to growth inhibition of a diverse set of cancer cell lines. This property together with the favourable pharmacokinetics and efficacy in vivo makes it a candidate for further pre-clinical and clinical development.

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…38 Similarly, the newly developed HDAC6-specific inhibitor C1A generated a significant growth inhibitory effect across a number of different cancer cell lines by induction of apoptosis rather than cell cycle arrest, in contrast to the effect of the pan-HDAC inhibitor SAHA. 51 Our findings showing only a moderate induction of apoptosis after inhibition of enzyme activity with even higher concentrations of Tubacin, but no induction of apoptosis after diminution of protein expression by siRNA knockdown, indicate that neither HDAC6 protein expression nor enzymatic activity are critical for urothelial carcinoma cells in general. However, some cell lines with low HDAC6 expression levels appeared to be more sensitive to HDAC6 inhibitors than others, suggesting that the cells require a critical level of enzyme activity that was undercut by the treatment.…”

“…Newly developed compound as such as HPOB or C1A are however reported to be selective for HDAC6 compared with HDAC10. 24,51 Subsequently, we compared the three compounds regarding their effects on the viability of urothelial cancer cell lines. In parallel with the data on the molecular effects, ST-80 appeared as the least potent compound with little efficacy even at high micromolar concentrations (100 μM).…”

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

“…Kaliszczak et al found that the novel small molecule hydroxamate preferentially inhibited HDAC6 activity and tumor growth. 43 Singh et al reported that HDAC activity was significantly inhibited in both A549 and H1299 cells treated with honokiol. 44 HeLa cells treated with TSA and PdNPs exhibited significant inhibition of HDAC activity.…”

“…72 Kaliszczak et al found that the novel small molecule C1A could inhibit HDAC activity, induce apoptosis, and inhibit proliferation of a panel of human tumor cell lines, as well as activate caspase-3 expression in vivo with subsequent fragmented DNA staining (TUNEL) increases of six-and seven-fold. 43 The HDACI honokiol inhibited the growth of both A549 and H1299 cells, and tumor cells from honokiol-treated mice were shown to undergo apoptotic cell death, as indicated by the TUNEL-positive cells as well as increases in the levels of pro-apoptotic Bax protein and cleaved caspase-3.…”

Flavones and Flavonols may have Clinical Potential as CK2 Inhibitors in Cancer Therapy

“…166 This finding may be of particular interest, in light of the fact that HDAC6, rather like CK2, works in multifarious ways to sustain malignant cellular behavior, and is emerging as a key target for cancer therapy. 172,173 It would be of interest to determine whether flavones/flavonols and sulforaphane might complement each other's efficacy in integrative cancer therapy.…”