Table 5.
Other natural molecules targeting HDAC in human cancers.
| Molecules (Origins) |
Used Models | Methods | Key Finding | Ref. |
|---|---|---|---|---|
| Isothiocyanate | ||||
| Phenethyl isothiocyanate (PEITC) (Not reported) | HCT116, SW480, and SW620 cells | Cell viability Western blot analysis Quantitative RT-PCR |
Induced stable changes in the expression profile of epigenetic erasers/writers. Induced hypomethylation of PcG target genes, which are generally hypermethylated in cancer. |
[244] |
| Phenethyl isothiocyanate (PEITC) (Purchased) | HT29 (Colon cells) | Determination of HDAC1 levels | PEITC + LA reduced the amount of aberrant crypt foci, as well as DNMT1 and HDAC1 levels (in vivo). | [245] |
| Sulforaphane (SFN) (Not reported) | MCF-7 and MDA-MB-231 | RT-PCR Western blot analysis HDAC and HAT activity Bisulfite sequencing analysis ChIP method |
Inhibited hTERT in both cells. Reduced the trimethyl-H3K9 and trimethyl-H3K27 in active chromatin indicators in a dose-dependent manner. |
[189] |
| Sulforaphane (SFN) (Purchased) | HeLa cells | DNMT and HDAC activity assessment Molecular docking study Bisulfite Modification and MSP RT-PCR |
Inhibited the activity of HDAC. Lowered the HDAC1 expression. Reactivated RAR, CDH1, DAPK1, and GSTP1 genes or elevated their expression. |
[207] |
| Sulforaphane (SFN) (Purchased) | A549 and H1299 (Lungs cells) | HDAC activity assay qRT-PCR Tumor xenografts |
Inhibited the activity of HDAC in lung cancer cells. Increased histone (H4 and H3) acetylation. Suppressed the activity of HDAC in vivo. |
[249] |
| Sulforaphane (SFN) (Purchased) | MCF-7 and MDA-MB-231 | HDACs activity assay | SFN + WA decreased HDAC expression. | [250] |
| Sulforaphane (SFN) (Purchased) | A549, HEK293, HT29 cells | Bisulfite genome sequencing RT-PCR Western blot analysis ChIP method HDAC and DNMT activity assessment |
Reduced CpG methylation in the miR-9-3 promoter region. Increased H3K4me1 enrichment at the miR-9-3 promoter. Induced the expression of miR-9-3. Reduced the epigenetic modifying enzymes’ expression and activity. |
[251] |
| Sulforaphane (SFN) (Purchased) | Breast cancer cells | RT-PCR Western blot analysis HDACs activity Global histone H3 acetylation quantification RNA sequencing analysis |
Increased gene transcription in tumor suppressor genes. Decreased the expression of tumor promoting genes. Decreased HDAC1 gene expression and enzymatic activity. Increased levels of histone acetylation. |
[252] |
| Sulforaphane (SFN) (Purchased) | HCT116 and RKO (Colon cells) | RT-PCR Western blot analysis HDAC activity |
Reduced the oncogenic hTERT mRNA, HDAC, miR-21, protein, and enzyme levels. | [253] |
| Sulforaphane (SFN) (Purchased) | MCF-7 and MDA-MB-231 | RT-PCR Western blot analysis HDAC activity |
SFN + GEN suppressed HDAC and HMT. SFN + GEN inhibited the expression of hTERT. |
[214] |
| Sulforaphane (SFN) (Not reported) | HepG2 and GAS cells | RNA-Seq analysis | Inhibited HDAC activity Downregulated chromatin profile regulating enzymes. |
[254] |
| Sulforaphane (SFN) (Purchased) | HepG2 cells | RNA extraction RNA-Seq analysis |
Inhibited HDAC activity. Methylation of oncogenic TF binding site motifs affected its activity. |
[249] |
| Quinones | ||||
| Laccaic acid (LA) (Purchased) | HT29 cells | HDAC activity assay | LA + PEITC reduced HDAC1 expression levels (in vivo). | [255] |
| Naphthazarin (Naph) (Purchased) | MCF-7 cells | RT-PCR Western blot analysis ChIP method |
Activated the p21 promoter by Naph + IR, by inhibiting the binding of multi-domain proteins. | [256] |
| Thymoquinone (Purchased) | JK cell line and MDA-MB-468 cells | Gene analysis RT-PCR analysis |
Downregulated numerous major epigenetic factors. | [257] |
| Carotenoid | ||||
| Astaxanthin (Purchased) | LNCaP cells | Cell viability test HDAC activity assay |
Inhibited HDAC activity in vitro. | [258] |
| Stilbenes | ||||
| Resveratrol (RSV) (Purchased) |
MDA MB 231 and MCF7 | Bisulfite conversion RT-PCR Western blot analysis |
Decreased HDAC1 protein levels. | |
| Resveratrol (RSV) (Purchased) |
HeLa, SiHa, and Caski cervical cells | Promoter methylation analysis Transient silencing of UHRF1 |
Induced PAX1 reactivation via its effect on HDAC, which is mediated through the downregulation of UHRF1, which may affect both histone acetylation and DNA methylation. | [259] |
| Resveratrol (RSV) (Not reported) |
B16F10 and Tumor-bearing mouse model | Western blot analysis Luciferase reporter assays Bisulfite sequencing PCR ChIP assay |
HDAC1 was recruited to the focal adhesion kinase (FAK) promoter region. | [260] |
| Resveratrol (RSV) (Purchased) |
MDA-MB-231 and MCF-7 cells | MTT assay Clonogenic method HDAC activity |
Reduced HDAC activity. | [261] |
| Curcumin (Cur) (Purchased) | Hep3B cells | Histone purification Histone acetylation assay Western blot analysis HAT assay HDAC assay RT-PCR |
Inhibited histone acetylation in the presence or absence of TSA. Inhibited the activity of HAT both in vitro and in vivo. Induced histone hypoacetylation in vivo. |
[262] |
| Curcumin (Cur) (Purchased) | Raji cells | Immunocytochemistry analysis Western blot analysis |
Reduced HDAC1, HDAC3, and HDAC8 protein expression levels. Increased Ac-histone H4 protein expression. |
[263] |
| Curcumin (Cur) (Purchased) | Raji cells | MTT assay Western blot analysis RT-PCR |
Decreased the amounts of HDAC3, HDAC1, and p300. Reversed the protection degradation of p300 and HDAC1 by MG-132. |
[264] |
| Curcumin (Cur) (Purchased) | Hela cells | HDAC activity assessment | Inhibited the HDAC activity (IC50 = 115 μM). | [265] |
| Curcumin (Cur) (Purchased) | DAOY, D283 Med, and D341 Med (medulloblastoma) | HDAC activity In vivo medulloblastoma xenografts |
Reduced the HDAC4 activity and expression. Increased tubulin acetylation. |
[266] |
| Curcumin (Cur) (Purchased) | LNCaP cells | Western blot analysis DNA extraction and bisulfite genomic sequencing PCR array RNA isolation and RT-PCR ChIP assay Histone H3 methylated lys27 ELISA HDAC activity assay |
Altered HDAC expression. Increased the expression of HDAC1, 4, 5, and 8, but decreased the HDAC3. Decreased HDAC activity. Decreased H3K27me3 enrichment at the Neurog1 promoter region and at the global level. |
[267] |
| Curcumin (Cur) (Purchased) | MCF7 and MDA MB 231 | Bisulfite conversion and MSP RT-PCR Western blot analysis |
Decreased protein levels of HDAC1. | |
| Curcumin (Cur) (Purchased) | HeLa, SiHa, and Caski cells | MTT assay Quantitative expression of PAX1, UHRF1, and p21 PAX1 promoter methylation analysis Transient silencing of UHRF1 |
Induced reactivation of PAX1, due to its effect on HDAC. | [259] |
| Calebin-A (Not reported) | MPNST cells | Cell proliferation Western blot analysis Flow cytometry ChIP assay |
Reduced the expression of acetyl H3 proteins. | [268] |
| Pterostilbene (PTS) (Purchased) | MDA-MB-157, HCC1806, and MCF10A | RT-PCR Western blot analysis SIRT activity assay DNMT activity |
RSV + PTS downregulated the SIRT1 (a type III HDAC). | [269] |
| Steroids | ||||
| Guggulsterone (Purchased) | Breast cancer cells | Bisulfite conversion and MSP RT-PCR Western blot analysis |
Decreased protein levels of HDAC1. | |
| Withaferin A (WA) (Purchased) | Breast cancer cells | Bisulfite conversion and MSP RT-PCR Western blot analysis |
Decreased HDAC1 and MeCP2 protein levels. | |
| Withaferin A (WA) (Purchased) | Breast cancer cells | qRT-PCR Western blot analysis HDAC activity |
WA + SFN decreased the HDAC activity and expression. | [250] |
| Phenolic acids | ||||
| Chlorogenic acid (Purchased) | Breast cancer cells | In vitro HDAC inhibition | Inhibited the HDAC activity (IC50 = 375 μM). | [265] |
| Caffeic acid (Purchased) | Breast cancer cells | In vitro HDAC inhibition | Moderately inhibited the HDAC activity (IC50 = 2.54 mM). | [265] |
| Secoiridoids | ||||
| Oleacein (Olea europaea L.) | U266, NCI-H929, RPMI-8226, MM1s, and JJN3 cells | Western blot analysis qRT-PCR HDAC activity |
Accumulated α-tubulin and acetylated histones. Downregulated multiple Class I/II HDACs. Inhibited HDACs with downregulation of Sp1. |
[270] |
| Tannins | ||||
| Ellagic acid (EA) (Purchased) | hASCs cells | qPCR Western blot analysis HDAC activity Immunocytochemistry of H3R17me2 and HDAC9 |
Inhibited HDAC 9 downregulation. Reduced the histone acetylation levels. |
[271] |
| Tanshinone | ||||
| Tanshinone IIA (Purchased) | HepG2-C8, JB6 P+, JB6-shNrf2 cells | Luciferase reporter activity assay RNA extraction and qRT-PCR Western blot analysis HDAC activity Bisulfite sequencing ChIP method |
Inhibited HDAC activity. | [272] |
| Others natural compounds | ||||
| Arsenic trioxide (AS2O3) (Purchased) | HeLa or HEK293T cells | Luciferase reporter assay RT-PCR ChIP method Flow cytometry |
Reduced global histone through direct binding. Increased HDAC4 expression. Inhibited the hMOF activity. |
[273] |
| Calcium glucarate (CAG) (Purchased) | Female mice cells | RT-PCR Bisulfite sequencing assay Western blot analysis |
Downregulated the levels of miR-203 Upregulated DNMT, HDAC, and promoter methylation of miR-203. |
[226] |
| Proanthocyanidins (GSPs) | Breast cancer cells | Western blot analysis HDAC activity |
Reduced HDAC activity. | [261] |
| Curcumol (Not reported) | CSLCs cells | qRT-PCR Western blot analysis Global DNA methylation HDAC activity Xenograft tumorigenicity assay Immunohistochemistry |
Blocked DNMT/HDAC activity and CSLC self-renewal in vivo and in vitro. Affected CLSCs by HDAC regulation. |
[274] |
| Selenium (Se) (Not reported) | LNCaP cells | HDAC activity | Reduced HDAC activity. No alteration of mRNA and protein levels of HDACs. Reduced methylated histone H3 on lysine 9 (H3-K9) levels. Increased acetylated H3-K9 levels. |
[275] |