Degraders in epigenetic therapy: PROTACs and beyond.

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy.

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

Correction: Curcumol inhibits breast cancer growth via NCL/ERα36 and the PI3K/AKT pathway.

Correction for 'Curcumol inhibits breast cancer growth via NCL/ERα36 and the PI3K/AKT pathway' by Zhou Lu Wei et al., Food Funct., 2023, https://doi.org/10.1039/d2fo02387c.

Mechanism of autophagy induced by osthole through PINK1/Parkin pathway in HeLa cells / 中国药理学通报

Aim To investigate the potential mechanism of osthole promoting autophagy in cervical cancer HeLa cells. Methods HeLa cells were treated with various concentrations of Osthole(0,10,20,40,80,160,240,320 mg·L-1). MTT was used to detect cell vitality. Transmission electron microscopy(TEM)was used to observe the morphology of HeLa cells after osthole intervention. Mondane sulfonyl cadaverine(MDC)staining was used to dectect the level of autophagy. Western blot was employed to analyze the expression levels of mitochondrial protein MFN1 and DPR1. JC-1 flourescence probe was applied to detect mitochondrial membrane potential. Flow cytometry was used to deteminet the release of reactive oxygen species(ROS). A transplanted tumor model of cervical cancer was established in vivo in nude mice. Western blot was used to detect the protein expression levels of PINK1,Parkin and LC3Ⅱ/. Results Osthole could inhibit the proliferation of HeLa cells significantly. Transmission electron microscopy showed that typical autophagosomes were formed in HeLa cells after osthole intervention. The fluorescence intensity of MDC was enhanced. The expression of mitochondrial fusion protein MFN1 was down-regulated after HeLa cells pretreated with osthole,and mitochondrial fission protein DRP1 was up-regulated. Mitochondrial membrane potential decreased. ROS production of HeLa cells was increased by flow cytometry,which could be reversed by autophagy inhibitor 3-MA. Tumor weight in nude mice was inhibited by osthole obviously,which might restrain cervical cancer. Western blot result indicated that the key factors of mitochondrial autophagy PINK1,Parkin and LC3Ⅱ/ratio were up-regulated in HeLa cells. Conclusions Osthole could induce autophagy in HeLa cells and its mechanism may be related to ROS production and PINK1/Parkin pathway.

Effects of EGCG on growth and expression of VEGF and PCNA in ovarian cancer xenografts of nude mice / 中国药理学通报

Aim To explore the effects of EGCG on xenografts of ovarian cancer in nude mice and its possible mechanism. Methods Nude mice xenografts of ovarian cancer SK0V3 cells were established and divided into five groups after tumor formation, in which three groups were given EGCG (10, 30, 50 mg • k g-

Boron and nitrogen codoped carbon dots as fluorescence sensor for Fe3+ with improved selectivity.

Carbon dots (CDs) are popular as fluorescence sensors, and metal ions are typical analytes. However, CDs used as fluorescent sensors for Fe3+ have some interferences coming from co-existed ions. In this study, we suspect that sp3 boron atom in phenylboronic acid group will be more compatible with Fe3+ to form coordination bonds, thereby increasing the selectivity to Fe3+. Hence, we designed and synthesized boron and nitrogen codoped carbon dots (BN-CDs) for detection of Fe3+ via a hydrothermal method using o-phenylenediamine (OPA) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylchloroformate as precursors. From the results, we found that BN-CDs had superior selectivity to Fe3+ in the presence of the other common interfering metal ions like Cu2+, Fe2+ and Pb2+. Besides, the obtained BN-CDs exhibited good water solubility, favorable photostability, excellent pH stability between pH 2-11, and strong fluorescence intensity with quantum yield up to 31.5 %. These excellent properties of carbon dots validate that our idea is feasible, and can be used for design CDs for Fe3+ detection. Quenching mechanism study showed the fluorescence intensity of BN-CDs could be dramatically quenched by Fe3+ through dynamic and static synergy process. Finally, the as prepared BN-CDs were successfully applied to the determination of Fe3+ in fetal bovine serum and lake water.

Red emissive boron and nitrogen co-doped "on-off-on" carbon dots for detecting and imaging of mercury(II) and biothiols.

Red emissive B,N co-doped carbon dots (BN-CDs) were hydrothermally synthesized from cresyl violet and boric acid. The BN-CDs exhibited excellent photostability, low cytotoxicity, excitation/emission maxima at 520/616 nm, and a relatively high quantum yield of 18%. The BN-CDs can binded to mercury(II), and this results in quenching of the red-colored fluorescence. However, on subsequent addition of the biothiol (such as cysteine, homocysteine or glutathione), fluorescence recovers. Therefore, the BN-CDs can be used as a multifunctional probe based on "on-off-on" fluorescence response for the detection of Hg(II) and biothiols. The following detection limits were accomplished: (a) Hg(II): 2.8 µM; (b) glutathione: 1.7 µM; (c) cysteine: 2.3 µM; (d) homocysteine: 3.0 µM. The BN-CDs also have been successfully applied for the imaging of Hg(II) and biothiols in HepG2 cells with excellent bio-compatibility. Graphical abstract Red emissive B,N co-doped carbon dots (BN-CDs) were synthesized through hydrothermal treatment of cresyl violet and boric acid. The BN-CDs can be used as a multifunctional probe based on "on-off-on" fluorescence response for detecting mercury(II) and biothiols in aqueous solution and living cells.