Table 4.
Anticancer effects of quinones with epigenetic targets.
| Bioactive Molecules | Origin | Experimental Methods | Key Results | References |
|---|---|---|---|---|
| d-antroquinonol | Not reported | Breast cancer cells (MCF-7, T-47D, and MDA-MB-231) DNMT1 enzyme activity assay Molecular modelling and docking Illumina methylation 450K array-based assay Real-time RT-PCR Western blot analysis Growth inhibition assay |
Inhibited DNMT1 in a dose-dependent manner but not DNMT3B. Bind to the catalytic domain of DNMT1. Decreased the methylation level of multiple TSGs, including the FANCC and CACNA1A genes. Increased the FANCC, CACNA1A mRNA, and protein expression levels. Inhibited the growth of breast cancer cells. |
[160] |
| Antrodia camphorate | Non-small cell lung cancer cell lines DNMT enzyme activity assay Cell viability and migration ability From flow cytometry analysis |
Inhibited the cell migration ability of CL1-5 cells. Induced high cytotoxicity toward different lung cancer cell lines. Up-regulated cyclin D2 gene expression in CL1-5 cells in time-dependent and dose-dependent manners. Caused cell cycle arrest at the G0/G1 phase. |
[161]. | |
| Antrodia camphorata | Breast cancer cell lines (MCF7, T47D, and MDA-MB-231) Molecular modeling and docking DNMT1 and DNMT3B methyltransferase activity assays MTT assay DNA methylation assay Real-time RT-PCR Western blot analysis |
Inhibited the growth of MCF7, T47D, and MDA-MB-231 breast cancer cells. Inhibited the migratory ability of MDA-MB-231 breast cancer cells. Inhibited the DNMT1 activity. Bind to the catalytic domain of DNMT1. Decreased the methylation status and reactivated the expression of multiple TSGs in MDA-MB-231 breast cancer cells. |
[162] | |
| Emodin | Purchased | Human bladder urothelial cell carcinoma Cell viability (MTT assay) Western blot analysis Semi-quantitative-PCR, quantitative real-time PCR cDNA microarray analysis ChIP assay |
Inhibited the cell growth of four bladder cancer cell lines in a dose- and time-dependent manner. Altered the epigenetic modifications. Suppressed pH3Ser10 and increased H3K27me3, contributing to gene silencing in bladder cancer cells. Repressed the oncogenic genes. Increased H3K27me3 and decreased pH3Ser10 modifications on the promoters of repressed genes, indicating that emodin reverses the cancer epigenetics towards normal epigenetic situations. |
[163] |
| Purchased | Human pancreatic cancer cell line PANC-1 Cell proliferation assay Dot-blot assay mRNA-sequence BSP assay Real-time PCR Western blot analysis |
Inhibited the growth of pancreatic cancer PANC-1 cells in a dose- and time-dependent manner. Inhibited the genomic 5mC expression in the PANC-1 cells. Altered the gene expression profile in the PANC-1 cells. Decreased the methylation levels of P16, RASSF1A, and ppENK. Increased the unmethylated status. |
[164] | |
| Not reported | Forty golden Syrian hamsters Tumor induction in the buccal pouches Western blot analysis |
Inhibited tumor formation. Reduced the severity of precancerous pathological lesions. Corrected the abnormalities in the expression pattern of Akt, MAPK, ERK, and DNMT in the buccal mucosa. |
[165] | |
| Purchased | Human pancreatic cancer cell line PANC-1 Cell proliferation assay Dot-blot assay BSP assay Fluorescent quantitative PCR (FQ-PCR) Western blot analysis |
Inhibited the growth of pancreatic cancer Panc-1 cells in a dose- and time-dependent manner. Caused slight demethylation. Emodin + 5-Aza-CdR significantly suppressed the expression of genome 5mC in PANC-1 cells. Emodin + 5-Aza-CdR induced more significant demethylation. Emodin + 5-Aza-CdR increased the expression levels of P16, RASSF1A, and ppENK more significantly. Emodin + 5-Aza-CdR reduced the expression levels of DNMT1 and DNMT3a more significantly. Emodin + 5-Aza-CdR enhanced the demethylation effect of 5-Aza-CdR by reducing the expression of methyltransferases. |
[166] | |
| Purchased | Lymphoma Raji cells Cell proliferation assay Flow cytometry Total RNA isolation and RT-qPCR analysis Luciferase reporter assay |
Decreased the percentage of Raji cell viability. Induced apoptosis. Increased the activation of caspase 3, caspase 9, and poly (ADP-ribose) polymerase through the downregulation of ubiquitin-like proteins containing PHD and RING domains 1 (UHRF1). Increased the level of DNMT3a, which inhibited the activity of p73 promoter 2 and decreased the levels of NH2-terminally truncated dominant-negative p73. |
[167] | |
| Not reported | Human breast cancer cell lines MDA-MB-453, MDA-MB-231, and MCF-7 Qpcr Western blot assay of hTERT, c-myc, and E2F1 proteins Methylation analysis by bisulfite modification |
Induced the telomere shortening and telomerase inhibition. Induced a demethylation of CpG islands in hTERT gene promoter in MDA-MB-453 and MCF-7 cells. Decreased the transcription of hTERT gene in the three breast cancer cell lines via the up-regulation of E2F1 and down-regulation of c-myc expressions. |
[168] | |
| Laccaic acid (LA) | Purchased | Human colon carcinoma cell line HT29 Induced colon cancer rat model Cell viability assay Cell cycle arrest analysis Determination of DNMT1, HDAC1, TNF-α, IL-6 levels |
LA + PEITC reduced the cell viability with apoptotic cell death (in vitro). LA + PEITC attenuated the number of aberrant crypt foci, fecal consistency score, IL-6, TNF-α, DNMT1, and HDAC1 levels (in vivo). |
[129] |
| Physcion 8-O-β-glucopyranoside (PG) | Not reported | Human HepG2 cells Cell viability assay Cell cycle analysis Cell apoptosis assay Overexpression of DNMT1 and Sp1 RT-PCR assay Western blot analysis |
Inhibited the growth and suppressed the invasion of HepG2 cells by down-regulating DNMT1 via ROS-dependent AMP-activated protein kinase (AMPK)- mediated modulation of transcription factor Sp1 | [169] |
| Not reported | Human breast cell line (MDA-MB-231) qRT-PCR Establishment of DNMT1- and Sp1-ovexpressing cell lines Knockdown of DNMT1 or Sp1 in MDA-MB-231 cells Western blot analysis In vivo lung metastasis model |
Inhibited the MDA-MB-231 cell proliferation. Inhibited the EMT process in MDA-MB-231 cells. Suppressed the DNMT1 expression via AMPK/Sp1 signaling. Reduced the lung metastasis of MDA-MB-231 cells in animal models. |
[170] | |
| Not reported | Testicular germ cell tumors (TGCTs) NCCIT and NTERA2 Cell cycle analysis Cell apoptosis assay RT-qPCR Western blot analysis Tumor induction in a xenograft mouse model |
Inhibited NTERA2 and NCCIT cell proliferation, blocked the cell cycle, and induced cell apoptosis. Suppressed LDH release, glucose consumption, lactate production, and ATP generation in NTERA2 and NCCIT cells. Increased the miR-199a expression in TGCTs Inhibited the tumor growth in vivo. |
[171] | |
| Shikonin | Purchased | MCF-7 and HeLa cells Luciferase reporter assay DNA fragmentation assay Cell proliferation assay |
Regulated p73, p16INK4A, ICBP90, and DNMT1 expression. Increased the p16INK4A promoter activity through the down-regulation of ICBP90. INK4A Induced the apoptosis in MCF-7 and HeLa cells. Induced the apoptosis via a caspase-dependent mechanism. |
[172] |
| Not reported | Human papillary thyroid cancer (PTC) cell line, TPC-1 Cytotoxicity assay DNMT1 gene knockdown and overexpression Transwell cell migration and invasion assay DNA extraction and MSP assay Western blot analysis |
Decreased the cell survival rate of TPC-1 cells in a dose-dependent manner. Inhibited the TPC-1 cell migration and invasion in a dose-dependent manner. Suppressed the methylation of PTEN, which reduced the expression of DNMT1 in a dose-dependent manner, and increased the expression of PTEN. Decreased the levels of protein expression of PTEN in TPC-1 cells. |
[173] | |
| Naphthazarin (Naph) | Purchased | Human breast cancer cell line, MCF-7 Cell proliferation assay and cell morphology RNA isolation and quantitative real-time PCR Western blot analysis ChIP assay Cell cycle analysis Apoptosis analysis |
Reduced the MCF-7 cell viability in a dose-dependent manner Naph + IR (ionizing radiation) increased the p53-dependent p21 (CIP/WAF1) promoter activity. Naph + IR activated the p21 promoter via the inhibition of binding of multi-domain proteins, DNMT1, UHRF1, and HDAC1. Naph + IR induced cell cycle arrest and apoptosis in MCF-7 cells. |
[174] |
| Nanaomycin A | Purchased | A549, HL60, and HCT116 cells DNA methylation analysis Methylation analysis of the RASSF1A promoter region RNA isolation and quantitative real-time PCR Western blot analysis Biochemical DNMT assay Molecular docking |
Reduced the global methylation levels in all three cell lines. Reactivated the transcription of the RASSF1A tumor suppressor gene. Revealed a selectivity toward DNMT3B. |
[174] |
| Thymoquinone | Purchased | Human leukemic T-cell line Jurkat (clone E6-1) Cell proliferation, viability, and apoptosis assays Cell cycle phase distribution analysis and quantitation of hypodiploid sub-G0/G1 cell population Assessment of DNA fragmentation pattern Western blot analysis |
Inhibited cell growth and induced cell cycle arrest of Jurkat cells. Induced the apoptosis in Jurkat cells. Induced the generation of ROS and the breakdown of ΔΨm in Jurkat cells. Up-regulated the p73 and down-regulated the UHRF1 in Jurkat cells. Induced the apoptosis, cell cycle arrest, and deregulation of p73 and UHRF1 expressions in Jurkat cells, which induced apoptosis via a caspase-dependent mechanism. |
[175] |
| Purchased | Human acute lymphoblastic leukemia (ALL) p53-mutated cells, Jurkat cells (clone E6-1) Cell apoptosis and proliferation assays Cell cycle analysis Western blot analysis |
Induced an initial down-regulation of PDE1A in the acute lymphoblastic leukemia Jurkat cell line with a subsequent down-regulation of UHRF1 via a p73-dependent mechanism. | [176] | |
| Purchased | Human cancer cell lines MDA-MB-435, HeLa and BT549, and mouse breast cancer cell line 4T1 Cell growth, migration, and invasion assay RNA extraction, RT-PCR, and qPCR analysis Protein extraction and western blot analysis Generation of breast tumor model of mouse Gene methylation assay |
Inhibited cancer cell growth, migration, and invasion in a dose-dependent manner. Decreased the transcriptional activity of the TWIST1 promoter and the mRNA expression of TWIST1, an EMT-promoting transcription factor. Decreased the expression of TWIST1-upregulated genes such as N-Cadherin and increased the expression of TWIST1-repressed genes such as E-Cadherin. Inhibited the growth and metastasis of cancer cell-derived xenograft tumors in mice but partially attenuated the migration and invasion in TWIST1-overexpressed cell lines. Enhanced the promoter DNA methylation of the TWIST1 gene in BT 549 cells. |
[177] | |
| Purchased | Cell lines, Kasumi-1, MV4-11, THP-1, and ML- 1 Leukemia- bearing mice Human DNMT1 homology modeling Docking simulation In vitro enzymatic activity assays Quantification of DNA methylation Colony formation and flow cytometry assays ChIP assay Western blot analysis RNA isolation and qPCR |
Interacted with the catalytic pocket of DNMT1 and competed with co-factor SAM/SAH for DNMT1 inhibition. Decreased the DNMT1 methylation activity in a dose-dependent manner with an apparent IC50 of 30 nM. Down-regulated the DNMT1, mechanistically, through dissociation of Sp1/NFkB complex from DNMT1 promoter. Reduced DNA methylation. Decreased the colony formation and increased the cell apoptosis via the activation of caspases. Induced leukemia regression. |
[178] | |
| Purchased | Human T lymphocyte cell line Jurkat, HL60, and HeLa cell lines Western blot analysis Apoptosis assays Real-time RT-PCR analysis |
Induced the degradation of UHRF1 (Ubiquitin-like containing PHD and Ring Finger 1), correlated with a sharp decrease in HAUSP (herpes virus-associated ubiquitin-specific protease) and an increase in cleaved caspase-3 and p73. Rapid ubiquitination of UHRF1, concomitantly. |
[179] | |
| Purchased | T-cell ALL JK cell line and MDA-MB-468 cell line, a human epithelial breast cancer cell line Cell proliferation assay RNA-seq and differentially expressed gene analysis Apoptosis assay Real-time RT-PCR analysis |
Down-regulated many key epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B, and KMT2A,B,C,D,E in Jurkat cells. Up-regulated several TSGs, such as DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4, and DDIT3. Up-regulated several downstream pro-apoptotic genes, such as RASL11B, RASD1, GNG3, BAD, and BIK. |
[180] |