Lapachol is a novel ribosomal protein S6 kinase 2 inhibitor that suppresses growth and induces intrinsic apoptosis in esophageal squamous cell carcinoma cells

Zu, Xueyin; Xie, Xiaodong; Zhang, Yuanyuan; Liu, Kangdong; Bode, Ann M.; Dong, Zigang; Kim, Dong Joon

doi:10.1002/ptr.6415

Cited by 14 publications

(7 citation statements)

References 37 publications

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“…JB6 mouse epithelial cells have been used to investigate the effects exerted by pharmacological compounds upon various signaling cascades, including epidermal growth factor (EGF)‐induced activation of the PI3K and MAPK pathways (Zu et al, 2019). To determine the effects of harmaline on intracellular signaling, serum‐starved JB6 cells were incubated with harmaline prior to treatment with EGF.…”

Section: Resultsmentioning

confidence: 99%

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Zhang

Shi

Xie

et al. 2021

Phytotherapy Research

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Harmaline is a naturally occurring β-carboline alkaloid that is isolated from Peganum harmala. It has shown efficacy in treating Parkinson's disease and has been reported to exhibit antimicrobial and anticancer properties. However, the molecular mechanism of harmaline in the context of esophageal squamous cell carcinoma (ESCC) has not been characterized. Here, we report that harmaline attenuates ESCC growth by directly targeting the mammalian target of rapamycin (mTOR). Harmaline strongly reduced cell proliferation and anchorage-independent cell growth. Additionally, harmaline treatment induced G2/M phase cell-cycle arrest through upregulation of p27. The results of in vitro and cell-based assays showed that harmaline directly inhibited the activity of mTOR kinase and the phosphorylation of its downstream pathway components. Depletion of mTOR using an shRNA-mediated strategy in ESCC cell lines indicated that reduced mTOR protein expression levels are correlated with decreased cell proliferation. Additionally, we observed that the inhibitory effect of harmaline was dependent upon mTOR expression. Notably, oral administration of harmaline suppressed ESCC patient-derived tumor growth in vivo. Taken together, harmaline is a potential mTOR inhibitor that might be used for therapeutically treating ESCC.

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Section: Resultsmentioning

confidence: 99%

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Zhang

Shi

Xie

et al. 2021

Phytotherapy Research

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“…Human tumor incidence and death have been steadily rising in recent years, and the incidence of esophageal cancer, in particular, remains high. One of the main reasons for tumor recurrence or difficulty in treatment is the weak immunogenicity or lack of expression of tumor antigens, and the body's immune tolerance to the tumor can lead to escape response when the tumor is attacked by the body, resulting in treatment failure [14][15][16][17][18]. Therefore, reducing tumor drug resistance and improving tumor immunogenicity is the key to successful esophageal tumor treatment.…”

Section: Discussionmentioning

confidence: 99%

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death

Huo

Pei

Wang

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. The focus of this research was to look at the effects of the combination of the lentinan (LNT) and oxaliplatin (Oxa) on the apoptosis of human esophageal cancer cells, as well as the underlying mechanism. Methods. LNT and Oxa were used to treat EC-109 human esophageal cancerous cells at various doses, and the cell survival rate was measured using the Cell Counting Kit-8 (CCK-8) assay. In addition, 24 h after treatment of EC-109 cells with a combination of LNT and Oxa, flow cytometry was used to analyze their apoptotic effect on these cells. Additionally, LNT on EC-109 cell apoptotic upshot was assessed via measuring the consequence of LNT on the mRNA and protein expression levels pertaining to immunogenic cell death factors CALR, HSP90, and HSP70 by qPCR (quantitative real-time polymerase chain reaction) and western blot analysis, correspondingly. Results. Cell proliferation was inhibited only when EC-109 cells were added with LNT at 1,200 μg/mL to the maximum concentrations, but the combination of LNT and Oxa at a low dose (800 μg/mL and 20 μM, respectively) significantly increased their sensitivity to Oxa and reduced their proliferation ( P < 0.05 ), and their apoptosis was significantly increased by LNT ( P < 0.05 ). The immunogenic cell death-related genes CALR, HSP90, and HSP70 had dramatically enhanced mRNA and protein expression levels after therapy with a combination of LNT and Oxa ( P < 0.05 ). Conclusion. These data imply that LNT increases the susceptibility of esophageal cancerous cells to Oxa by driving EC-109 cells to display immunogenic death. Therefore, LNT combined with Oxa may be an effective method in esophageal cancer management.

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“…Later, the anticancer potential of lapachol and its analogs have been extensively explored ( 15 , 16 ). These studies reported the ability of lapachol to induce mitochondria-mediated cellular apoptosis by activating caspases and PARP ( 17 ). Lapachol analogs also downregulate the expression of the c-Myc, cyclin D1 and cyclin B1, which induce cell cycle arrest in the S and G2/M phases resulting in inhibition of tumor cell proliferation ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

et al. 2021

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Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF6 (1) and [Ru(Lap)(dppm)(phen)]PF6 (2) [Lap = lapachol, dppm = 1,1′-bis(diphosphino)methane, bipy = 2,2′-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex (2) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex (2) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (2), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy.

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Lapachol is a novel ribosomal protein S6 kinase 2 inhibitor that suppresses growth and induces intrinsic apoptosis in esophageal squamous cell carcinoma cells

Cited by 14 publications

References 37 publications

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

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