Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway

Wong, Chin Piow; Seki, Ari; Horiguchi, Kaori; Shoji, Tetsuro; Arai, Takashi; Nugroho, Alfarius Eko; Hirasawa, Yusuke; Sato, Fumiaki; Kaneda, Toshio; Morita, Hiroshi

doi:10.1021/acs.jnatprod.5b00258

Cited by 21 publications

(16 citation statements)

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“…5 ). PRAS40 is a metabolism protein bound to mTOR complex, and acts as the receptor of mTOR, PRAS40 also can regulate the proliferation in various cell lines ( 12 , 13 ). The results of this work indicated that PRAS40 can be regulated by LicA-induced-ROS in HCCs, and when HCCs were cotreated with LicA and NAC, the change of PRAS40 expression level was inhibited ( Fig.…”

Section: Resultsmentioning

confidence: 99%

LicA induces autophagy through ULK1/Atg13 and ROS pathway in human hepatocellular carcinoma cells

et al. 2018

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Chemotherapy is the best choice for the vast majority of hepatocellular carcinoma patients at late stage, but few effective chemotherapy drugs are available in clinic. Licochalcone A (LicA) is a new chemotherapy drug inducing apoptosis as Bcl-2 inhibitor, but few studies report on LicA-induced autophagy. This study investigated the phenomenon and mechanisms of LicA-induced autophagy looking for a targeted combination drug. Human hepatocellular carcinoma cells (HCCs) were treated with LicA, to detect markers of autophagy and to investigate the mechanisms. In order to investigate the role of reactive oxygen species (ROS) in LicA-induced autophagy, ROS, glutathione (GSH) and O2− were measured in LicA treated HCCs, and antioxidant N-Acetyl-L-cysteine (NAC) was cotreated with LicA in HCCs, then mechanisms of ROS-induced autophagy was investigated in LicA or LicA combined with NAC treated HCCs. Finally, the LicA-induced apoptosis was detected in LicA combined with NAC treated HCCs. We first report that LicA can induce autophagy through ULK1/Atg13 and ROS pathway in HCCs, suppression of LicA-induced ROS through antioxidant NAC can enhance LicA-induced apoptosis, promoting the function of LicA killing HCCs. LicA can activate the ULK1/Atg13 complex which is upstream of autophagy, additionally, LicA also can promote ROS generation, ROS trigger the expression level of TSC1/2 complex, PRAS40, CTMP, PP2A, PDK1 and Rubicon change, these molecules are upstream of autophagy. In conclusion, LicA can induce autophagy through ULK1/Atg13 and ROS pathway in HCCs, LicA combined with NAC can enhance LicA-induced apoptosis. Our results may provide a novel design for clinical hepatocellular carcinoma therapy trials.

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Section: Resultsmentioning

confidence: 99%

LicA induces autophagy through ULK1/Atg13 and ROS pathway in human hepatocellular carcinoma cells

et al. 2018

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“…Interestingly, some of the bisindole alkaloids showed cytotoxicity rather than those with monomeric units [2][3][4]. Various indole alkaloids that exhibited diverse molecular skeleton and significant diverse bioactivity have been reported from our laboratory [5][6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 98%

Two new bisindole alkaloids from Tabernaemontana macrocarpa Jack

et al. 2021

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Graphic abstract Two new bisindole alkaloids, bisnaecarpamines A ( 1 ) and B ( 2 ), possessing a vobasine-sarpagine type skeleton were isolated from the bark of Tabernaemontana macrocarpa Jack. Their structures were elucidated by extensive spectroscopic methods and chemical correlation. The absolute configurations of compounds 1 and 2 were established using TDDFT-ECD calculation of the selected isomers. Bisnaecarpamine A exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC 50 value of 28.8 µM. Supplementary Information The online version contains supplementary material available at 10.1007/s11418-021-01510-4.

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“…Bisindole alkaloids possess antibacterial, anti-inflammatory, antimalarial and anticancer properties [7]. Bisleuconothine A modulates the AKT-mTOR signaling pathway and induces autophagosomes [8]. The present investigation was carried out to study the effects of bisleuconothine A and hyperbaric oxygen on traumatic neuronal injury in rats.…”

Section: Introductionmentioning

confidence: 99%

Bisleuconothine A potentiates the effect of hyperbaric oxygen therapy against traumatic brain injury by enhancing P2X4 protein expressions

Meng¹,

Zhang²,

Li³

et al. 2020

Trop. J. Pharm Res

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Purpose: To investigate the effect of bisleuconothine A (BA), alone and in combination with hyperbaric oxygen (HO), on traumatic brain injury (TBI) in rats. Methods: Traumatic brain injury (TBI) was induced by dropping a 200-g weight of steel on the left anterior frontal areas of Sprague-Dawley rats. The synergistic effect of BA and HO was determined by assessing neurological score, as well as parameters of oxidative stress and inflammation, expressions of P2X4 protein and other proteins, and levels of reactive oxygen species (ROS) in the brain tissues of TBI rats. Results: Neurological function score, levels of inflammatory mediators and oxidative stress parameters were significantly reduced in rats treated with BA alone, and in those treated with a combination of BA and HO, when compared with untreated TBI rats (p < 0.01). Moreover, treatment with BA alone, and BA-HO combination attenuated the altered protein expressions of P2X4, Akt, PI3K and TLR-4 in the TBI rats, and also upregulated the mRNA expression of P2X4 in the brain tissue, when compared with untreated TBI rats (p < 0.01). Conclusion: These results suggest that BA, when used alone or in combination with HO, reduces neuronal injury through upregulation of the protein expression of P2X4 in rats with traumatic brain injury. Thus, BA may be used clinically with HO therapy for the management of traumatic injury. Keywords: Bisleuconothine A, Hyperbaric oxygen, Neuronal injury, Oxidative stress, Inflammatory mediators

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Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway

Cited by 21 publications

References 50 publications

LicA induces autophagy through ULK1/Atg13 and ROS pathway in human hepatocellular carcinoma cells

LicA induces autophagy through ULK1/Atg13 and ROS pathway in human hepatocellular carcinoma cells

Two new bisindole alkaloids from Tabernaemontana macrocarpa Jack

Bisleuconothine A potentiates the effect of hyperbaric oxygen therapy against traumatic brain injury by enhancing P2X4 protein expressions

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