Liensinine

The plantule of Nelumbo nucifera Gaertn.

A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission.[Pubmed:26114658]

Autophagy. 2015;11(8):1259-79.

Autophagy inhibition has been widely accepted as a promising therapeutic strategy in cancer, while the lack of effective and specific autophagy inhibitors hinders its application. Here we found that Liensinine, a major isoquinoline alkaloid, inhibits late-stage autophagy/mitophagy through blocking autophagosome-lysosome fusion. This effect is likely achieved via inhibiting the recruitment of RAB7A to lysosomes but not to autophagosomes. We further investigated the effects of autophagy inhibition by Liensinine on the therapeutic efficacy of chemotherapeutic drugs and found that cotreatment of Liensinine markedly decreased the viability and increased apoptosis in breast cancer cells treated with various chemotherapeutic agents. Mechanistically, we found that inhibition of autophagy/mitophagy by Liensinine enhanced doxorubicin-mediated apoptosis by triggering mitochondrial fission, which resulted from dephosphorylation and mitochondrial translocation of DNM1L. However, blocking autophagosome/mitophagosome formation by pharmacological or genetic approaches markedly attenuated mitochondrial fission and apoptosis in cells with combinatatorial treatment. Moreover, Liensinine was synergized with doxorubicin to inhibit tumor growth in MDA-MB-231 xenograft in vivo. Our findings suggest that Liensinine could potentially be further developed as a novel autophagy/mitophagy inhibitor, and a combination of Liensinine with classical chemotherapeutic drugs could represent a novel therapeutic strategy for treatment of breast cancer.

In vitro characterization of ABC transporters involved in the absorption and distribution of liensinine and its analogs.[Pubmed:24036064]

J Ethnopharmacol. 2013 Nov 25;150(2):485-91.

ETHNOPHARMACOLOGICAL RELEVANCE: Lotus plumule, the dried young cotyledon and radicle of the Nelumbo nucifera Gaertn. (Fam. Nymphaeaceae) ripe seed, is a famous Traditional Chinese Medicine to remove heat from the heart, anchor the mind, improve seminal emission, and arrest bleeding for centuries in China. Liensinine and its analogs neferine and isoLiensinine are the major active components in lotus plumule. Aim of the study is to investigate the association of Liensinine, neferine, and isoLiensinine with efflux transporters. MATERIALS AND METHODS: Caco-2, MDCK, MDCK-MDR1, and MDCK-MRP2 were used as cell models for the transcellular transport and accumulation studies. RESULTS: The results obtained in Caco-2 cells suggested that P-glycoprotein (P-gp) might be involved in transcellular transport. Cellular accumulation and transport experiments were further performed in MDCK-MDR1 cells. GF120918 and cyclosporine A were found to completely inhibit the efflux, and the net efflux ratios of these alkaloids exhibited saturation over the concentration range. No significant differences in Liensinine accumulation and transport were observed between MDCK and MDCK-MRP2 cells. CONCLUSIONS: These results demonstrated that Liensinine, neferine, and isoLiensinine are substrates of P-gp, whereas MRP2 is not involved in the transport process, suggesting that P-gp might be responsible for the absorption and distribution of the 3 alkaloids.

Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis.[Pubmed:22508050]

Cell Physiol Biochem. 2012;29(3-4):431-42.

Liensinine and neferine, a kind of isoquinoline alkaloid, can antagonize the ventricular arrhythmias. The human ether-a-go-go-related gene (hERG) is involved in repolarization of cardiac action potential. We investigated the effects of Liensinine and neferine on the biophysical properties of hERG channel and the underlying structure-activity relationships. The effects of Liensinine and neferine were examined on the hERG channels in the stable transfected HEK293 cells using a whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. The pharmacokinetics and tissue distribution determination of Liensinine and neferine in rats were determined by a validated RP-HPLC method. Liensinine and neferine induced decrease of current amplitude in dose-dependent. Liensinine reduced hERG tail current from 70.3+/-6.3 pA/pF in control group to 56.7+/-2.8 pA/pF in the 1 muM group, 53.0+/-2.3 pA/pF (3 muM) and 17.8+/-0.7 pA/pF (30 muM); the corresponding current densities of neferine-treated cells were 41.9+/-3.1 pA/pF, 32.3+/-3.1 pA/pF and 16.2+/-0.6 pA/pF, respectively. Neferine had binding affinity for the open and inactivated state of hERG channel, Liensinine only bound to the open state. The inhibitory effects of Liensinine and neferine on hERG current were attenuated in the F656V or Y652A mutant channels. Neferine distributed more quickly than Liensinine in rats, which was found to be in higher concentration than Liensinine. Both Liensinine and neferine had no effect on the generation and expression of hERG channels. In conclusion, neferine is a more potent blocker of hERG channels than Liensinine at low concentration (<10 muM), which may be due to higher hydrophobic nature of neferine compared with Liensinine. Neferine may be safety even for long-term treatment as an antiarrhythmic drug.

[Effect of berberine, liensinine and neferine on HERG channel expression].[Pubmed:23672049]

Zhongguo Zhong Yao Za Zhi. 2013 Jan;38(2):239-44.

OBJECTIVE: Immunofluorescence and Western blot methods were adopted for qualitative and quantitative detections of the effect of different concentrations of berberine, Liensinine and neferine on the expression of stable transfection in HERG potassium channel in HEK-293 cells, as well as the effect of different concentrations of berberine on protein expression of Ikr channel in cardiac muscular tissues, in order to investigate the anti-arrhythmic mechanism of berberine, Liensinine and neferine. METHOD: Western blot method was used to detect protein expression of HERG channel in HERG-HEK cells. Immunofluorescence method as well as confocal laser microscope were used to detect the effect of different concentrations of berberine, Liensinine and neferine on protein expression of HERG channel. Western blot method was used to detect the effect of different concentrations of berberine on protein expression of Ikr channel in cardiac muscular tissues as well as the effect of berberine, Liensinine and neferine on protein expression of stable transfection in HERG potassium channel in HEK-293 cells. RESULT: Western blot experiment manifested that stable transfection of HEK293 cells containing HERG genes could increase protein expression of HERG channel. Berberine (10, 30 micromol x L(-1)) remarkably inhibited protein expression of HERG channel in HERG-HEK cells (P < 0.01). Berberine (10, 20 mg x kg(-1)) also inhibited protein expression of Ikr channel in rat ventricular tissues (P < 0.05). Liensinine (3, 10, 30 micromol x L(-1)) increased protein expression of HERG channel in HERG-HEK cells (P < 0.05). Neferine showed no effect on protein expression of HERG channel in HERG-HEK cells. CONCLUSION: The stably transfection of HERG-HEK cells can increase protein expression of HERG channel. Berberine shows inhibitory effect on protein expressions of in vitro HERG-HEK cells and Ikr channel in rat ventricular tissues. Liensinine improves protein expression of HERG channe in HERG-HEK cells. Neferine shows no effect on protein expression of HERG channel.

Liensinine is an autophagy/mitophagy inhibitor. Liensinine, a major isoquinoline alkaloid, extracted from the seed embryo of Nelumbo nucifera Gaertn, has a wide range of biological activities, including anti-arrhythmias, anti-hypertension, anti-pulmonary fibrosis, relaxation on vascular smooth muscle, etc.

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