LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer.

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.

Discovery of acridine-based LSD1 inhibitors as immune activators targeting LSD1 in gastric cancer.

LSD1 is overexpressed in various cancers and promotes tumor cell proliferation, tumor expansion, and suppresses immune cells infiltration and is closely associated with immune checkpoint inhibitors therapy. Therefore, the inhibition of LSD1 has been recognized as a promising strategy for cancer therapy. In this study, we screened an in-house small-molecule library targeting LSD1, an FDA-approved drug amsacrine for acute leukemia and malignant lymphomas was found to exhibit moderate anti-LSD1 inhibitory activity (IC50 = 0.88 µM). Through further medicinal chemistry efforts, the most active compound 6x increased anti-LSD1 activity significantly (IC50 = 0.073 µM). Further mechanistic studies demonstrated that compound 6x inhibited the stemness and migration of gastric cancer cell, and decreased the expression of PD-L1 (programmed cell death-ligand 1) in BGC-823 and MFC cells. More importantly, BGC-823 cells are more susceptible to T-cell killing when treated with compound 6x. Moreover, tumor growth was also suppressed by compound 6x in mice. Altogether, our findings demonstrated that acridine-based novel LSD1 inhibitor 6x may be a lead compound for the development of activating T cell immune response in gastric cancer cells.

Physiological response and oxidative transformation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) by a Chlorella isolate.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous, toxic and persistent pollutants in environments. Microalgae frequent exposed to these pollutants may possess defense mechanisms against their toxicity and have the ability to metabolize them, thus are important in bioremediation. This study investigated the mechanism of a Chlorella isolate to degrade BDE-47, a common PBDE congener, and its subcellular responses to BDE-47 stress. Results showed that 86-98% of the spiked BDE-47 was removed by Chlorella via adsorption, uptake and metabolism. BDE-47 was metabolized through debromination, hydroxylation and methoxylation. The oxidative transformation to hydroxylated products was the initial and main metabolic process. BDE-47 induced the production of hydrogen peroxide (H2O2) in cell wall, plasma membrane and chloroplast of Chlorella, and such increase was regulated by nicotinamide adenine dinucleotide phosphate oxidase and H2O2-producing peroxidases (PODs). The activity of H2O2-consuming PODs and the content of glutathione were also significantly enhanced to detoxify the oxidative stress.

[Protection of Transcutaneous Acupoint Electrical Stimulation for Brain Injury Undergoing Intervention: a Clinical Observation].

OBJECTIVE: To observe the effect of transcutaneous acupoint electrical stimulation (TAES) combined dexmedetomidine on hemodynamic of intracranial aneurysmal subarachnoid hemorrhage patients undergoing intervention, and their protection for brain Injury. METHODS: Totally 108 intracranial aneurysmal subarachnoid hemorrhage patients undergoing intervention were randomly assigned to the electroacupuncture (EA) group and the control group according to random digit table, 54 in each group. All patients were anesthetized with dexmedetomidine. Patients in the EA group were needled at bilateral Neiguan (PC6), Lieque (LU7), and Yunmen (LU2). Parameter setting was as follows: The dilatational wave at 1. 5 Hz, strength 2 - 4 mA, 30 min. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were compared between the two groups immediately after entry into the room (T0), after administration (T1), intubating (T2), resuscitation (T3), extubation (T4), and leaving the operating room (T5). Levels of S100ß protein (S100ß) and neuron specific enolase (NSE) were compared between the two groups at T0, immediately after surgery (T6), 6 h after operation (T7), 12 h after operation (T8), and 24 h after operation (T9). RESULTS: Compared with the same group at T0, SBP, DBP, MAP, and HR were significantly reduced in the two groups at T1-T5(P <0. 05), serum levels of S100ß and NSE in the two groups were significantly increased at T6-T9 (P<0. 05). Compared with the control group at T1 - T5, SBP, DBP, MAP, and HR decreased in the EA group (P <0. 05). Compared with the control group at T6-T9, serum levels of S100ß and NSE decreased in the EA group (P <0. 05). CONCLUSION: TAES combined dexmedetomidine could effectively maintain stable hemodynamics of intracranial aneurysmal subarachnoid hemorrhage patients undergoing intervention, and regulate their serum levels of S100ß and NSE.

[Immune effects of three different programs for revaccination among adults of non- and hypo-responders to hepatitis B vaccine].

OBJECTIVE: To investigate the immune effects of three different programs for revaccination among adults of non- and hypo-responders to recombinant Hepatitis B vaccine. METHODS: Those who were once immunized with recombinant Hepatitis B vaccine more than one standard schedule (0, 1, and 6 months) in two years and negative for Hepatitis B markers were randomly given three-different projects for revaccination. 34 adults of A group were given GM-CSF 300 microg by subcutaneous injection for the first day, then 10 microg each time by intramuscular route for routine immune method. 33 adults of B group were given Hepatitis B vaccine 20 microg each time. 33 adults of C group were given Hepatitis B vaccine 10 microg each time. The blood samples were collected before the first injection and in 1, 2 and 8 months following the first injection to test Anti-HBs. RESULTS: At T1, the anti-HBs positive conversion rate of group A, B and C was 26.47%, 48.48% and 18.18% respectively (chi-2 = 7.20, P = 0.027). At T8, the anti-HBs positive conversion rate of group A (64.71%) and group B (75.76%) were higher than group C (39.39%), and there was significant difference (chi-2 = 9.07, P = 0.011). At T1, the anti-HBs level of group B (417.00 +/- 69.36) was higher than that of group A (203.74 +/- 79.56). At T2, the anti-HBs level of group B (458.17 +/- 64.09) was higher than that of group C (257.86 +/- 76.60). At T8, the anti-HBs level of group A (501.48 +/- 70.00) and group B (532.73 +/- 68.82) were higher than those of group C (256.12 +/- 75.39) (t =4.27, P = 0.0173). CONCLUSION: Schemes of augmentation doses of Hepatitis B vaccine and being combined with GM-CSF should be in effect for non- and hypo-responders to Hepatitis B vaccine.

[Study on rhGM-CSF as adjuvant in revaccination among adults of non-and hyporesponders to hepatitis B vaccine].

OBJECTIVE: To investigate the effect of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) as adjuvant on immune response in adults of non-and hyporesponders to hepatitis B vaccine. METHODS: Those who were once immunized with recombined yeast gene hepatitis B vaccine more than one standard scheme in two years and negative for hepatitis B markers were randomly sorted as group A and group B. 33 adults of group A were given hepatitis B vaccine 10 microg each time. The immune procedure was 0, 1 and 6 month. 34 adults of group B were given rhGM-CSF 300 microg for the first day, then 10 microg each time for routine immune. The blood samples were collected before the first injection and in 1, 2 and 8 months (T1, T2, T8) following the first injection to test Anti-HBs. RESULTS: Anti-HBs positive conversion rates of group A and B at T8 was 39.39% and 64.71% respectively (P = 0.038). Anti-HBs levels of group B at T1, T2, T8 were (113.85 +/- 198.56) mIU/ml, (312.40 +/- 349.44) mIU/ml, (427.74 +/- 411.58) mIU/ml (P = 0.001). There was significant difference between group A and B in T8 Anti-HBs levels (P = 0.010). CONCLUSION: Better immune response was found in the group of rhGM-CSF with hepatitis B vaccine. So rhGM-CSF can induce the immune respond to hepatitis B vaccine.