Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo.
Ontology highlight
ABSTRACT:
SUBMITTER: Fan J
PROVIDER: S-EPMC7028916 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Osteosarcoma is one of the most malignant neoplasms in adolescents, and it generally develops multidrug resistance. Escin, a natural mixture of triterpene saponins isolated from Aesculus hippocastanum (horse chestnut), has demonstrated potent anti-tumour potential in vitro and in vivo. In the present study, we found that escin inhibited osteosarcoma proliferation in a dose- and time-dependent manner. Additionally, escin-induced apoptosis was evidenced by the increased expression of caspase-related proteins and the formation of apoptotic bodies. Escin also induced autophagy, with elevated LC3, ATG5, ATG12 and Beclin expression as well as autophagosome formation. Inhibition of escin-induced autophagy promoted apoptosis. Moreover, p38 mitogen-activated protein kinases (MAPKs) and reactive oxygen species (ROS) were activated by escin. A p38 MAPK inhibitor partially attenuated the autophagy and apoptosis triggered by escin, but a ROS scavenger showed a greater inhibitory effect. Finally, the therapeutic efficacy of escin against osteosarcoma was demonstrated in an orthotopic model. Overall, escin counteracted osteosarcoma by inducing autophagy and apoptosis via the activation of the ROS/p38 MAPK signalling pathway; these findings provide evidence for escin as a novel and potent therapeutic for the treatment of osteosarcoma.
| S-EPMC5682655 | biostudies-literature
Project description:Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. In the present study, we investigated the anticancer effect of honokiol (HNK), an active component isolated and purified from the magnolia officinalis on human osteosarcoma cells. Our results showed that honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells. The types of cell death induced by honokiol were primarily autophagy and apoptosis. Furthermore, honokiol induced G0/G1 phase arrest, elevated the levels of glucose-regulated protein (GRP)-78, an endoplasmic reticular stress (ERS)-associated protein, and increased the production of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Furthermore, pretreatment of osteosarcoma cells with PD98059, an inhibitor of ERK1/2, inhibited honokiol-induced apoptosis and autophagy. Finally, honokiol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that honokiol caused G0/G1 phase arrest, induced apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells. Honokiol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.
| S-EPMC5833587 | biostudies-literature
Project description:Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. Celastrol, a triterpene from traditional Chinese medicine, has been proved to possess potent anti-tumor effect on various cancers. However, the effect of celastrol on human osteosarcoma and the underlying mechanisms remains to be elucidated. We reported here that celastrol could inhibit cell proliferation by causing G2/M phase arrest. Exposure to celastrol resulted in the activation of caspase-3, -8, and -9, indicating that celastrol induced apoptosis through both extrinsic and intrinsic pathways. Autophagy occurred in celastrol-treated cells as evidenced by formation of autophagosome and accumulation of LC3B-II. The celastrol-induced cell death was remarkably restored by the combination of autophagy and apoptosis inhibitors. Furthermore, inhibition of apoptosis enhanced autophagy while suppression of autophagy diminished apoptosis. Celastrol also induced JNK activation and ROS generation. The JNK inhibitor significantly attenuated celastrol-triggered apoptosis and autophagy while ROS scavenger could completely reverse them. The ROS scavenger also prevented G2/M phase arrest and phosphorylation of JNK. Importantly, we found that celastrol had the similar effects on primary osteosarcoma cells. Finally, in vivo, celastrol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that celastrol caused G2/M phase arrest, induced apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells. Celastrol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.
| S-EPMC4669742 | biostudies-literature
Project description:Pseudomonas aeruginosa infection can induce alveolar macrophage apoptosis and autophagy, which play a vital role in eliminating pathogens. These two processes are usually not independent. Recently, autophagy has been found to interact with apoptosis during pathogen infections. Nevertheless, the role of autophagy in P. aeruginosa-infected cell apoptosis is unclear. In this study, we explored the impact of P. aeruginosa infection on autophagy and apoptosis in RAW264.7 cells. The autophagy activator rapamycin was used to stimulate autophagy and explore the role of autophagy on apoptosis in P. aeruginosa-infected RAW264.7 cells. The results indicated that P. aeruginosa infection induced autophagy and apoptosis in RAW264.7 cells, and that rapamycin could suppress P. aeruginosa-induced apoptosis by regulating the expression of apoptosis-related proteins. In addition, rapamycin scavenged the cellular reactive oxygen species (ROS) and diminished p-JNK, p-ERK1/2 and p-p38 expression of MAPK pathways in RAW264.7 cells infected with P. aeruginosa. In conclusion, the promotion of autophagy decreased P. aeruginosa-induced ROS accumulation and further attenuated the apoptosis of RAW264.7 cells through MAPK pathway. These results provide novel insights into host-pathogen interactions and highlight a potential role of autophagy in eliminating P. aeruginosa.
| S-EPMC7556189 | biostudies-literature
Project description:BACKGROUND/AIM:Numerous studies on various cancer cell lines have reported that direct exposure to non-thermal plasma treatment using plasma-activated medium (PAM) can be applied as a novel technology for cancer therapy. In this study, we investigated the inhibitory effects of PAM on Aspc1 pancreatic cancer cells and the mechanisms responsible for the cell death observed. MATERIALS AND METHODS:A colony-formation, sphere-formation, wound-healing and transwell assays, immunocytochemistry and western blot analysis were used monitor effects of PAM. RESULTS:PAM induced a greater cytotoxic effect in pancreatic cancer cells compared to that induced in NIH3T3 cells and 293T cells, and significantly inhibited colony and sphere formation, and cell migration of Aspc1 cells. Furthermore, PAM treatment increased the accumulation of reactive oxygen species (ROS) and reduced the mitochondrial membrane potential in Aspc1 cells. In addition, PAM treatment down-regulated the AKT serine/threonine kinase 1/signal transducer and activator of transcription 3 signaling pathway and induced ROS-dependent cellular autophagy. CONCLUSION:Our findings suggest that PAM can induce apoptosis of Aspc1 cells through ROS-dependent autophagy and may be a candidate for use in pancreatic cancer therapeutics.
| S-EPMC6984097 | biostudies-literature
Project description:Introduction:The leaves of Morus alba L is a traditional Chinese medicine widely applied in lung diseases. Moracin N (MAN), a secondary metabolite extracted form the leaves of Morus alba L, is a potent anticancer agent. But its molecular mechanism remains unveiled. Objective:In this study, we aimed to examine the effect of MAN on human lung cancer and reveal the underlying molecular mechanism. Methods:MTT assay was conducted to measure cell viability. Annexin V-FITC/PI staining was used to detect cell apoptosis. Confocal microscope was performed to determine the formation of autophagosomes and autolysosomes. Flow cytometry was performed to quantify cell death. Western blotting was used to determine the related-signaling pathway. Results:In the present study, we demonstrated for the first time that MAN inhibitd cell proliferation and induced cell apoptosis in human non-small-cell lung carcinoma (NSCLC) cells. We found that MAN treatment dysregulated mitochondrial function and led to mitochondrial apoptosis in A549 and PC9 cells. Meanwhile, MAN enhanced autophagy flux by the increase of autophagosome formation, the fusion of autophagsomes and lysosomes and lysosomal function. Moreover, mTOR signaling pathway, a classical pathway regualting autophagy, was inhibited by MAN in a time- and dose-dependent mannner, resulting in autophagy induction. Interestingly, autophagy inhibition by CQ or Atg5 knockdown attenuated cell apoptosis by MAN, indicating that autophagy serves as cell death. Furthermore, autophagy-mediated cell death by MAN can be blocked by reactive oxygen species (ROS) scavenger NAC, indicating that ROS accumulation is the inducing factor of apoptosis and autophagy. In summary, we revealed the molecular mechanism of MAN against lung cancer through apoptosis and autophagy, suggesting that MAN might be a novel therapeutic agent for NSCLC treatment.
| S-EPMC7235196 | biostudies-literature
Project description:AimsIsoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, has previously been reported to have anti-tumor effects in vivo and in vitro. However, the mechanisms whereby ISL exerts its anticancer effects remain poorly understood in hepatocellular carcinoma (HCC).PurposeIn the present study, we investigated the anticancer efficacy and associated mechanisms of ISL in HCC MHCC97-H and SMMC7721 cells.ResultsWe found that ISL inhibited cell viability and proliferation and induced apoptosis in a dose- and time-dependent manner in liver cancer lines. Furthermore, ISL could activate autophagy in HCC cells, and the autophagy inhibitor HCQ enhances ISL-induced apoptosis in HCC cells. Additionally, ISL induced apoptosis and autophagy through inhibition of the PI3K/Akt/mTOR pathway. Most importantly, in a xenograft tumor model in nude mice, data showed that the administration of ISL decreased tumor growth and concurrently promoted the expression of LC3-II and cleaved-caspase-3. Interestingly, we found that ISL inhibits mTOR by docking onto the ATP-binding pocket of mTOR (ie, it competes with ATP). We thus suggest that mTOR is a potential target for ISL inhibition of hepatocellular carcinoma development, which could be of interest for future investigations.ConclusionTaken together, the results reveal that ISL effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction in vivo and in vitro, probably via the PI3K/Akt/mTOR pathway. ISL may be a potential therapeutic agent for hepatocellular carcinoma.
| S-EPMC7585813 | biostudies-literature
Project description:Aims: Peiminine has been reported to have various pharmacological properties, including anticancer activity. In this study, we investigated the effect of this alkaloid on osteosarcoma and explored the underlying mechanisms. Methods: To evaluate the antiosteosarcoma effects of peiminine in vitro, cell viability was assessed by CCK-8 and live/dead assays; the effects of the drug on apoptosis and the cell cycle were examined by flow cytometry; the effects on cell migration and invasion were detected by wound healing and Transwell assays, respectively, while its effects on autophagy were observed by transmission electron microscopy and an LC3 fluorescent puncta formation assay. The role of autophagy in the peiminine-mediated effects in osteosarcoma cells was evaluated by CCK-8 assay and western blotting after the application of the autophagy inhibitor chloroquine. The effect of peiminine on reactive oxygen species (ROS) production was analyzed using fluorescence confocal microscopy and spectrophotometry. Additionally, peiminine-treated osteosarcoma cells were exposed to SP600125, a JNK inhibitor, and N-acetylcysteine, a ROS scavenger, after which the contribution of the ROS/JNK signaling pathway to osteosarcoma was assessed using cell viability and LC3 fluorescent puncta formation assays, flow cytometry, and western blotting. A xenograft mouse model of osteosarcoma was generated to determine the antitumor effects of peiminine in vivo. Results: Peiminine suppressed proliferation and metastasis and induced cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells. These anticancer effects of peiminine were found to be dependent on intracellular ROS generation and activation of the JNK pathway. In line with these results, peiminine significantly inhibited xenograft tumor growth in vivo. Conclusions: Peiminine induced G0/G1-phase arrest, apoptosis, and autophagy in human osteosarcoma cells via the ROS/JNK signaling pathway both in vitro and in vivo. Our study may provide an experimental basis for the evaluation of peiminine as an alternative drug for the treatment of osteosarcoma.
| S-EPMC8633898 | biostudies-literature
Project description:Bruceine D is one of the active components of Brucea javanica (L.) Merr., which is widely used to treat cancer in China. The aim of the present study was to evaluate the potential effect of bruceine D against non?small?cell lung cancer (NSCLC) cells and delineate its underlying mechanisms. The results indicated that treatment with bruceine D markedly inhibited the proliferation of wild?type NSCLC cells and epidermal growth factor receptor?mutant cells in a dose? and time?dependent manner, and significantly decreased the colony?forming ability and migration of A549 cells. Hoechst 33342 staining and flow cytometric analysis demonstrated that treatment with bruceine D effectively induced apoptosis of A549 cells. In addition, the proapoptotic effect of bruceine D was found to be associated with G0?G1 cell cycle arrest, accumulation of intracellular reactive oxygen species (ROS) and malondialdehyde, depletion of glutathione levels and disruption of mitochondrial membrane potential. Additionally, pretreatment with N?acetylcysteine, a ROS scavenger, significantly attenuated the bruceine D?induced inhibition in A549 cells. Western blotting demonstrated that treatment with bruceine D significantly suppressed the expression of the anti?apoptotic proteins Bcl?2, Bcl?xL and X?linked inhibitor of apoptosis, enhanced the expression levels of apoptotic proteins Bax and Bak, and inhibited the expression of pro?caspase?3 and pro?caspase?8. Based on these results, it may be suggested that inhibition of A549 NSCLC cell proliferation by bruceine D is associated with the modulation of ROS?mitochondrial?mediated death signaling. This novel insight may provide further evidence to verify the anticancer efficacy of B. javanica, and support a role for bruceine D in the anti?NSCLC treatment.
| S-EPMC6844635 | biostudies-literature
Project description:OBJECTIVES:SL4, a chalcone-based compound, exhibits clearly inhibitory effects on HIF-1 and has been shown to effectively suppress tumour invasion and angiogenesis in vitro and in vivo. Here, studies were conducted to determine SL4's anti-apoptotic effects and its underlying mechanisms, in human cancer cells. MATERIALS AND METHODS:Cytotoxicity, apoptotic induction and its involved mechanisms of SL4 were investigated using normal cells, cancer cells and mouse xenograft models. The role of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) signalling in SL4-induced apoptosis was explored by manipulating specific scavenger or signalling inhibitors, in cultured cells. RESULTS:SL4 significantly inhibited cell population growth of human cancer cell lines but exhibited lower cytotoxicity against normal cells. In addition, SL4 effectively induced apoptosis of Hep3B and MDA-MB-435 cells by activating procaspase-8, -9 and -3, and down-regulating expression levels of XIAP, but did not affect HIF-1 apoptosis-related targets, Survivin and Bcl-XL. Further study showed that SL4 also reduced mitochondrial membrane potential and promoted generation of ROS. ROS generation and apoptotic induction by SL4 were blocked by NAC, a scavenger of ROS, suggesting SL4-induced apoptosis via ROS accumulation. We also found that MAPKs, JNK and p38, but not ERK1/2, to be critical mediators in SL4-induced apoptosis. SP600125 and SB203580, specific inhibitors of JNK kinase and p38 kinase, significantly retarded apoptosis induced by SL4. Moreover, anti-oxidant NAC blocked activation of JNK and p38 induced by SL4, indicating that ROS may act as upstream signalling of JNK and p38 activation. It is noteworthy that animal studies revealed dramatic reduction (49%) in tumour volume after 11 days SL4 treatment. CONCLUSIONS:These data demonstrate that SL4 induced apoptosis in human cancer cells through activation of the ROS/MAPK signalling pathway, suggesting that it may be a novel lead compound, as a cancer drug candidate, with polypharmacological characteristics.
| S-EPMC6496741 | biostudies-literature