Triazole–Dithiocarbamate Based Selective Lysine Specific Demethylase 1 (LSD1) Inactivators Inhibit Gastric Cancer Cell Growth, Invasion, and Migration

Zheng, Yi-Chao; Duan, Ying-Chao; Ma, Junxia; Xu, Ruimin; Zi, Xiaolin; Lv, Wen-Lei; Wang, Mengmeng; Ye, Xian-Wei; Zhu, Shun; Mobley, David L.; Zhu, Yanyan; Wang, Junwei; Li, Jinfeng; Wang, Zhi-Ru; Zhao, Wen; Liu, Hong‐Min

doi:10.1021/jm401002r

Cited by 201 publications

(134 citation statements)

References 86 publications

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“…LSD1 is regarded as a predictive marker for malignant transformation as the overexpression of LSD1 is associated with poor differentiation and poor survival (31,(34)(35)(36). LSD1 promotes the growth, invasion and migration of cancer cells (28), while inhibiters of LSD1 suppress the proliferation, migration and invasion of cancer cells (30,32,37).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of LSD1 suppresses the proliferation, tumorigenicity and invasion of papillary thyroid carcinoma K1 cells

et al. 2016

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Abstract. The present study aimed to evaluate the effects of lysine-specific demethylase 1 (LSD1) downregulation, induced by small interfering RNA (siRNA) transfection, on the proliferation, colony formation, migration and invasion of the papillary thyroid carcinoma K1 cell line. The siRNA targeting LSD1 and scrambled non-targeting siRNA were each transfected into papillary thyroid carcinoma K1 cells. Downregulation of LSD1 mRNA and protein level was evaluated by reverse transcription-quantitative polymerase chain reaction, and immunocytochemical (ICC) analysis and western blotting, respectively. A Cell Counting kit-8 assay was applied to estimate the effect of LSD1-siRNA on cell growth. Migration and invasion abilities were estimated by Transwell chamber assay. A soft agar colony formation assay was performed to estimate the effect of LSD1-siRNA on tumorigenicity in vitro. ICC data showed that LSD1 protein was strongly expressed in the blank and control K1 cells compared with the LSD1-siRNA cells (F=15.192, P<0.01). Compared with the control cells, cells transfected with siRNA targeting LSD1 exhibited significant downregulation of LSD1 mRNA (t=6.845, P<0.01) and protein (F=53.764, P<0.01) levels. siRNA targeting LSD1 also downregulated cell proliferation following transfection for 24, 48 and 72 h (t=4.777, P<0.001; t=3.302, P=0.003; and t=3.017, P=0.006, respectively). Compared with the control group, the amount of cell invasion was gradually reduced in the LSD1-siRNA group (t=12.301, P<0.01). The number of migrating cells was significantly higher in the negative control group compared with the LSD1-siRNA group (t=7.911, P<0.01), and the ability of colony formation in the LSD1-siRNA cells was notably reduced in the soft agar formation assay (t=3.612, P=0.005). siRNA targeting LSD1 efficiently inhibits the proliferation, colony formation, migration and invasion of papillary thyroid carcinoma K1 cells.

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Section: Discussionmentioning

confidence: 99%

Downregulation of LSD1 suppresses the proliferation, tumorigenicity and invasion of papillary thyroid carcinoma K1 cells

et al. 2016

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“…The dialysis assay was done as published [31]. Briefly, 1.5 μg of SIRT1 recombinant was incubated with 60 μM compound 3a, 10 μM EX-527, or DMSO for 30 min.…”

Section: Ultrafiltration and Dialysis Experimentsmentioning

confidence: 99%

“…In our previous report, we found a group of 1,2,3-triazole-dithiocarbamate hybrids as LSD1 inhibitors [31,32]. After that, we tried to optimized these compounds as a more potent LSD1 inhibitor, and a series of novel 1,4-bispiperazinecarbodithioic acid -methyl esters were synthesized and their anti-tumor activity were evaluated.…”

Section: Identification Of Compound 3a As a Potential Sirt1 Inhibitormentioning

confidence: 99%

“…Among them, compound 3a performed the most potent anti-proliferation activity in human gastric cancer cell line MGC-803 with IC50=11.15 μM. We further evaluated its LSD1 inhibitory effect by biochemical assay as published [31]. To our surprise, compound 3a performed no inhibitory effect against LSD1 recombinant.…”

Section: Identification Of Compound 3a As a Potential Sirt1 Inhibitormentioning

confidence: 99%

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1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors

Zheng

Wang²,

Zhao

et al. 2016

Cell Physiol Biochem

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Background/Aims: Human SIRT1 is reported to be involved in tumorgenesis, mainly due to its modulating effect on p53 by deacetylation on lysine382. A large quantity of SIRT1 inhibitors was applied in chemotherapeutic study, but few of them were applied into clinical trials. Methods and Results: In the current study, a novel series of compounds with 1,4-bispiperazinecarbodithioic acid methyl esters scaffold were characterized to have inhibitory potency to SIRT1 by molecular docking and biochemical evaluation. Further cell level study revealed that one of the most potent SIRT1 inhibitors, compound 3a, is cell active. It can upregulate the amount of p53 by accumulating the K382 acetylation of p53, which lead to the stabilization of p53 in human gastric cancer cell line MGC-803 cells. Meanwhile, we also found compound 3a can inactivate SIRT2 in cells, which suggests the compound as a non-selective SIRT inhibitor. Conclusion: All these findings indicate that compound 3a is a potent, reversible and cell active SIRT1 inhibitor and deserves further investigation as an anticancer agent or a biological tool.

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“…1). As-pharmaceuticals, they have been used as drugs and prodrugs for the different type of biological activities such as anti-microbial, 13 anticancer, 14 antiprotozoal, 15 antileprosy, 16 antitubercular, 17 anti-fungal, 18 anti-alzheimer, 19 and contraceptive agents 20 …”

Section: Introductionmentioning

confidence: 99%

Triton-B catalyzed, efficient and solvent-free approach for the synthesis of dithiocarbamates

Zaidi¹,

Chaturvedi²,

Singh³

et al. 2017

10.5267/j.ccl

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A novel one-pot, solvent-free method for the synthesis of dithiocarbamates was developed through the reaction of corresponding alkyl halides, amines and carbon disulfide employing catalytic amount of benzyl trimethyl ammonium hydroxide (Triton-B). The reaction conditions are milder with extremely simple work-up procedures than the reported methods, afforded high yields (82-98%) of the desired products.

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Triazole–Dithiocarbamate Based Selective Lysine Specific Demethylase 1 (LSD1) Inactivators Inhibit Gastric Cancer Cell Growth, Invasion, and Migration

Cited by 201 publications

References 86 publications

Downregulation of LSD1 suppresses the proliferation, tumorigenicity and invasion of papillary thyroid carcinoma K1 cells

Downregulation of LSD1 suppresses the proliferation, tumorigenicity and invasion of papillary thyroid carcinoma K1 cells

1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors

Triton-B catalyzed, efficient and solvent-free approach for the synthesis of dithiocarbamates

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