Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway

Tian, Xin; Dai, Shun‐Dong; Sun, Jing; Jiang, Shenyi; Sui, Chengguang; Meng, Fandong; Li, Yan; Fu, Liye; Jiang, Tao; Wang, Yang; Su, Jia; Jiang, Youyu

doi:10.1155/2015/546210

Cited by 23 publications

(17 citation statements)

References 30 publications

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“…Therefore, cancer treatment by means of enhancing intracellular ROS production may be considered an effective approach. Natural compounds, such as nimbolide and bufalin, are able to induce pancreatic cancer cell apoptosis by increasing ROS levels (31,32). The present study demonstrated that treatment with 25 µM moscatilin led to an increase in ROS generation; however, moscatilin-inhibited cell viability was abolished by NAC, thus suggesting that ROS is responsible for the proapoptotic effects of moscatilin on pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway

Zhang

Fang

et al. 2017

Molecular Medicine Reports

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Moscatilin is a bibenzyl derivative extracted from the Dendrobium aurantiacum var. denneanum, which has traditionally been used as an immunomodulatory treatment in China. The present study was designed to determine whether moscatilin is a pro-apoptotic agent in pancreatic cancer, and to elucidate the underlying mechanisms. The apoptotic and anti-proliferative effects of moscatilin on pancreatic cancer cells were determined in vitro using biochemical assays, such as the MTT assay, colony formation assay, Hoechst staining and DNA fragmentation assay, and in vivo using Panc-1 pancreatic cancer xenografts. Western blotting was also conducted to evaluate the expression levels of B-cell lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax), Bcl2 homologous antagonist killer (Bak), caspase 3, cleaved-caspase 3, poly (ADP-ribose) polymerase, p-c-Jun N-terminal kinase (JNK)/stress-activated protein kinases (SAPK) and JNK/SAPK in response to moscatilin. We used DCFH-DA to detect the production of reactive oxygen species (ROS) induced by moscatilin. The present study demonstrated that moscatilin markedly inhibited pancreatic cancer cell viability and induced cell apoptosis in a concentration-dependent manner. Conversely, moscatilin did not affect the cell viability of human umbilical vein endothelial cells at the comparable dosage. Treatment with moscatilin suppressed clonogenicity of Panc-1 cells in a concentration-dependent manner. Furthermore, a decrease in Bcl2 expression, and an increase in the expression levels of Bak and Bax, was detected following treatment with moscatilin, resulting in an increase in the proapoptotic/anti-apoptotic expression ratio (Bax/Bcl2) in Panc-1 cells. Moscatilin also induced activation of the caspase-dependent mitochondrial apoptotic pathway. In addition, moscatilin enhanced cellular ROS production and induced activation of JNKSAPK signaling pathway. Conversely, pretreatment with the ROS scavenger N-acetylcysteine or the JNK/SAPK-specific inhibitor SP600125 prevented moscatilin-mediated reductions in cell viability. Furthermore, moscatilin inhibited tumor growth in nude mice bearing Panc-1 cells, without apparent toxicity. In conclusion, these results demonstrated that moscatilin may induce pancreatic cell apoptosis, and therefore may be considered a potential therapeutic agent for the treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway

Zhang

Fang

et al. 2017

Molecular Medicine Reports

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“…This indicates that T-oligo–initiated DDRs are specific to cancer cells and may be due to changes in telomere physiology that are common among cancers. Silencing hTERT in oral cancer cells is accompanied by caspase-9/-3 cleavage, DNA damage responses, and decreased cell viability [79]. It may be possible that T11’s antiproliferative response is in some way hTERT-dependent or hTERT-mediated due to its homology to the telomere, and therefore selective to cells that express the telomerase enzyme.…”

Section: Telomere Homolog Oligonucleotidesmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

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Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effe...

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“…The mitochondrial pathway consists of the main signal in cell apoptosis. [32][33][34] In the start-up phase, the mitochondria release cytochrome c, which activates the caspase family and then starts cascades in the cytoplasm. 35 To date, at least 15 members of the caspase family have been identified.…”

Section: Discussionmentioning

confidence: 99%

Icarisid II inhibits the proliferation of human osteosarcoma cells by inducing apoptosis and cell cycle arrest

et al. 2017

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Icarisid II, one of the main active components of Herba Epimedii extracts, shows potent antitumor activity in various cancer cell lines, including osteosarcoma cells. However, the anticancer mechanism of icarisid II against osteosarcoma U2OS needs further exploration. This study aims to investigate further antitumor effects of icarisid II on human osteosarcoma cells and elucidate the underlying mechanism. We cultivated human osteosarcoma USO2 cells in vitro using different concentrations of icarisid II (0-30 µM). Cell viability was detected at 24, 48, and 72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis. Cell cycle was tested by flow cytometry after treatment with icarisid II for 48 h. Annexin V-allophycocyanin and 7-aminoactinomycin D staining were conducted to detect cell apoptosis. Quantitative real-time polymerase chain reaction and Western blot assay were performed to measure the levels of genes and proteins related to cell cycle and apoptosis. Results showed that icarisid II significantly inhibited the proliferation and induced apoptosis of human osteosarcoma U2OS cells. The half maximal inhibitory concentration values were 14.44, 11.02, and 7.37 µM at 24, 48, and 72 h, respectively. Cell cycle was arrested in the G2/M phase in vitro. In addition, icarisid II upregulated the expression levels of P21 and CyclinB1 whereas downregulated the expression levels of CyclinD1, CDC2, and P-Cdc25C, which were related to cell cycle arrest in U2OS cells. The cell apoptotic rate increased in a dose-dependent manner after treatment with icarisid II for 48 h. Icarisid II induced apoptosis by upregulating Bax, downregulating Bcl-2, and activating apoptosis-related proteins, including cleaved caspase-3, caspase-7, caspase-9, and poly (ADP-ribose) polymerase. These data indicate that icarisid II exhibits an antiproliferation effect on human osteosarcoma cells and induces apoptosis by activating the caspase family in a time- and dose-dependent manner in vitro. Therefore, icarisid II may be used as a candidate agent for the clinical treatment of osteosarcoma in the future.

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Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway

Cited by 23 publications

References 30 publications

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway

Treating Cancer by Targeting Telomeres and Telomerase

Icarisid II inhibits the proliferation of human osteosarcoma cells by inducing apoptosis and cell cycle arrest

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