المؤلفون: Su, Min-Xia, Xu, Yu-Lian, Jiang, Xiao-Ming, Huang, Mu-Yang, Zhang, Le-Le, Yuan, Luo-Wei, Xu, Xiao-Huang, Zhu, Qi, Gao, Jian-Li, Lu, Jia-Hong, Chen, Xiuping, Huang, Ming-Qing, Wang, Yitao, Lu, Jin-Jian

المصدر: Acta Pharmaceutica Sinica B; Mar2022, Vol. 12 Issue 3, p1240-1253, 14p

مصطلحات موضوعية: GINSENOSIDES, EVEROLIMUS, ANTINEOPLASTIC agents, GINSENG, MTOR inhibitors, LUNG cancer

مستخلص: The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62⁺ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62⁺ aggresomes-triggered paraptosis and revealed a unique function of c-MYC. Eve-Rh2 up-regulates the expression of c-MYC, which mediates the accumulation of TRIB3/P62⁺ aggresomes bypassing the classical c-MYC/MAX pathway, thereby triggering paraptosis and ultimately inhibiting tumor progression. [Display omitted] [ABSTRACT FROM AUTHOR]

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المؤلفون: Lu, Zhaoming, Shi, Xiaojing, Gong, Fanghua, Li, Shenglei, Wang, Yang, Ren, Yandan, Zhang, Mengyin, Yu, Bin, Li, Yan, Zhao, Wen, Zhang, Jianying, Hou, Guiqin

المصدر: Acta Pharmaceutica Sinica B; Jun2020, Vol. 10 Issue 6, p1004-1019, 16p

مصطلحات موضوعية: SQUAMOUS cell carcinoma, TREATMENT effectiveness, MTOR inhibitors, CELL cycle, CELL proliferation

مستخلص: Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/ mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo. Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC. This study demonstrated that mTORC2 subunit, RICTOR, and p-AKT (Ser473) have hyperactivity in esophageal squamous cell carcinoma (ESCC) and promotes its development. Moreover, down-regulation of RICTOR can improve the sensitivity of ESCC cells to the pan-mTOR inhibitor PP242 as well as mTORC1 inhibitor RAD001. Image 1 [ABSTRACT FROM AUTHOR]

: Copyright of Acta Pharmaceutica Sinica B is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Li, Guodong, Boyle, Joshua William, Ko, Chung-Nga, Zeng, Wu, Wong, Vincent Kam Wai, Wan, Jian-Bo, Chan, Philip Wai Hong, Ma, Dik-Lung, Leung, Chung-Hang

المصدر: Acta Pharmaceutica Sinica B; May2019, Vol. 9 Issue 3, p537-544, 8p

مصطلحات موضوعية: MTOR inhibitors, THERAPEUTICS, STARVATION, MORPHOLOGY, LIVER

مستخلص: We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases. We identified aurone derivative 1a as an ATP-competitive inhibitor of Vps34 inhibitor. 1a prevented autophagy in human cells induced either by starvation or by an mTOR inhibitor. In vivo examination showed that 1a was able to promote p62 accumulation without affecting the morphology of mice heart and liver. fx1 [ABSTRACT FROM AUTHOR]

: Copyright of Acta Pharmaceutica Sinica B is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Chung-Nga Ko, Joshua William Boyle, Dik-Lung Ma, Philip Wai Hong Chan, Wu Zeng, Jian-Bo Wan, Chung-Hang Leung, Vincent Kam Wai Wong, Guodong Li

المصدر: Acta Pharmaceutica Sinica B, Vol 9, Iss 3, Pp 537-544 (2019)

مصطلحات موضوعية: Original article, 0303 health sciences, Virtual screening, In silico, lcsh:RM1-950, fungi, Autophagy, Antagonist, Discovery and development of mTOR inhibitors, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, lcsh:Therapeutics. Pharmacology, 0302 clinical medicine, chemistry, In vivo, 030220 oncology & carcinogenesis, Aurone, Liver damage, General Pharmacology, Toxicology and Pharmaceutics, 030304 developmental biology

الوصف: We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases. KEY WORDS: Autophagy, Natural products, Vps34, Inhibitor, Structure-based virtual screening, Vesicle trafficking, Heart or liver damage, Aurone derivative

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b9e7227930a63a3398ad30c17dc4b4e9Test
https://doi.org/10.1016/j.apsb.2019.01.016Test