Natural protoberberine alkaloids, identified as potent selective LSD1 inhibitors, induce AML cell differentiation.

Natural protoberberine alkaloids were first identified and characterized as potent, selective and cellular active lysine specific demethylase 1 (LSD1) inhibitors. Due to our study, isoquinoline-based tetracyclic scaffold was identified as the key structural element for their anti-LSD1 activity, subtle changes of substituents attached to the core structure led to dramatic changes of the activity. Among these protoberberine alkaloids, epiberberine potently inhibited LSD1 (IC50 = 0.14 ± 0.01 µM) and was highly selective to LSD1 over MAO-A/B. Furthermore, epiberberine could induce the expression of CD86, CD11b and CD14 in THP-1 and HL-60 cells, confirming its cellular activity of inducing acute myeloid leukemia (AML) cells differentiation. Moreover, epiberberine prolonged the survival of THP-1 cells bearing mice and inhibited the growth of AML cells in vivo without obvious global toxicity. These findings give the potential application of epiberberine in AML treatment, and the isoquinoline-based tetracyclic scaffold could be used for further development of LSD1 inhibitors.

Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ±â€¯0.3 µM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.

Sanggenon O induced apoptosis of A549 cells is counterbalanced by protective autophagy.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.

Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance. Herein, our findings revealed a novel mechanism of LSD1 neddylation and its contribution to decreasing GC cell stemness and chemoresistance. Taken together, our findings may whistle about the future application of neddylation inhibitors.

Targeting neddylation E2s: a novel therapeutic strategy in cancer.

Ubiquitin-conjugating enzyme E2 M (UBE2M) and ubiquitin-conjugating enzyme E2 F (UBE2F) are the two NEDD8-conjugating enzymes of the neddylation pathway that take part in posttranslational modification and change the activity of target proteins. The activity of E2 enzymes requires both a 26-residue N-terminal docking peptide and a conserved E2 catalytic core domain, which is the basis for the transfer of neural precursor cell-expressed developmentally downregulated 8 (NEDD8). By recruiting E3 ligases and targeting cullin and non-cullin substrates, UBE2M and UBE2F play diverse biological roles. Currently, there are several inhibitors that target the UBE2M-defective in cullin neddylation protein 1 (DCN1) interaction to treat cancer. As described above, this review provides insights into the mechanism of UBE2M and UBE2F and emphasizes these two E2 enzymes as appealing therapeutic targets for the treatment of cancers.