Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells

Mo, En-Pan; Zhang, Rongrong; Xu, Jun; Zhang, Huan; Wang, Xiaoxiong; Tan, Qiutong; Liu, Fanglan; Jiang, Ren‐Wang; Cai, Shaohui

doi:10.1016/j.bbrc.2016.08.011

Cited by 15 publications

(18 citation statements)

References 26 publications

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“…In addition, cell cycle progression is regulated by cyclin-dependent kinases (CDKs) and their regulatory cyclins. Cyclin B1 and CDK1 are involved in controlling the G2/M checkpoint [ 13 ], and some anti-tumor drugs induce G2/M arrest by decreasing the expression of cyclin B1 and CDK1[ 14 , 15 ]. In our study, we found that treatment with AT-I leads to the G2/M arrest in A2780 cells with the down-regulation of cellular cyclin B1 and CDK1, suggesting that AT-I prevented A2780 cell mitosis by inhibition of cyclin B1 and CDK1 expression, and induction of cell cycle at G2/M phase, which contribute to the inhibitory effects.…”

Section: Discussionmentioning

confidence: 99%

Anti-Tumor Effects of Atractylenolide-I on Human Ovarian Cancer Cells

et al. 2017

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BackgroundThe aim of this study was to investigate the effects of Atractylenolide-I (AT-I), a naturally occurring sesquiterpene lactone isolated from Atractylodes macrocephala Koidz, on human ovarian cancer cells.Material/MethodsThe viability and anchorage-independent growth of ovarian cancer cells were evaluated using MTT and colony formation assay, respectively. Cell cycle and apoptosis were detected with flow cytometry analysis. The level of cyclin B1 and CDK1 was measured using qPCR and ELISA analysis. The expression of Bax, cleaved caspase-9, cleaved caspase-3, cytochrome c, AIF, and Bcl-2, and phosphorylation level of PI3K, AKT, and mTOR were determined with Western blot analysis.ResultsAT-I decreased the cell viability and suppressed anchorage-independent growth of A2780 cells. Cell cycle was arrested in G2/M phase transition by AT-I treatment, which was related to decreased expression of cyclin B1 and CDK1 in a dose-dependent manner. In addition, the treatment induced apoptosis, as shown by up-regulation of Bax, cleaved caspase-9, cleaved caspase-3, and cytosolic release of cytochrome c and AIF, and down-regulation of Bcl-2, in a dose-dependent manner. Then, the effects of AT-I on PI3K/Akt/mTOR pathways were examined to further investigate the underlying anti-cancer mechanism of AT-I, and the results showed that treatment with AT-I significantly decreased the phosphorylation level of PI3K, Akt, and mTOR.ConclusionsThis study demonstrated that AT-I induced cell cycle arrest and apoptosis through inhibition of PI3K/Akt/mTOR pathway in ovarian cancer cells. These results suggest that AT-I might be a potential therapeutic agent in the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Anti-Tumor Effects of Atractylenolide-I on Human Ovarian Cancer Cells

et al. 2017

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“…Cisplatin is the most active platinum agent for patients with advanced lung cancer and early-stage patients who require adjuvant therapy (15). However, after treatment for a certain period of time, most patients develop cisplatin resistance (16,17).…”

Section: Introductionmentioning

confidence: 99%

Src homology phosphotyrosyl phosphatase 2 mediates cisplatin-related drug resistance by inhibiting apoptosis and activating the Ras/PI3K/Akt1/survivin pathway in lung cancer cells

Tang

Luo

et al. 2017

Oncol Rep

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Cisplatin resistance is a major cause of chemotherapeutic failure in lung cancer patients. Unraveling the molecular mechanisms underlying cisplatin (CDDP) resistance is important in lung cancer therapeutics. To explore the role of Src homology phosphotyrosyl phosphatase 2 (SHP2) in the development of cisplatin resistance in lung cancer and the underlying mechanism, we established stable SHP2‑overexpressing H446‑SHP2-OE cells and SHP2‑knockdown H446/CDDP‑SHP2-shRNA cells derived from H446 and H446/CDDP (cisplatin-resistant) parental lung cancer cells. The cell viability and apoptosis of these cells exposed to CDDP were observed to determine the influence of SHP2 on drug resistance. In addition, the expression of SHP2, Ras, Akt1 and survivin was assessed by western blot analysis after the lung cancer cells were challenged by cisplatin or silenced by Ras siRNA. As a result, the 50% inhibitory concentration (IC50) of the H446-SHP2-OE cells exposed to CDDP increased from 1.01 to 1.218 µg/ml vs. the H446-control vector cells. The percentage of apoptotic cells was smaller in the H446-SHP2-OE cells vs. the H446-control vector cells after cisplatin challenge. In addition, the expression of Ras, pAkt1, Akt1 and survivin in the H446/CDDP cells was significantly increased vs. the H446 cells. Furthermore, the IC50 of the H446/CDDP‑SHP2‑shRNA cells exposed to CDDP decreased from 11.92 to 4.382 µg/ml vs. the H446/CDDP‑mock cells. There were significantly more apoptotic cells among the H446/CDDP‑SHP2-shRNA cells vs. the H446/CDDP-mock cells exposed to cisplatin. A smaller percentage of the H446/CDDP-SHP2-shRNA cells vs. the H446/CDDP‑mock cells was observed. In addition, the expression of pAkt1 and survivin in the H446, H446/CDDP and H446/CDDP-mock cells was increased upon exposure to cisplatin however, a corresponding change was not observed in the H446/CDDP-SHP2-shRNA cells. Upon Ras RNA silencing with cisplatin, the Ras expression was significantly decreased in the H446, H446-SHP2-OE and H446/CDDP cells. However, upon Ras RNA interference, the SHP2 expression was not significantly changed, but the expression of Akt1, pAkt1 and survivin was significantly increased in the H446-SHP2-OE and H446/CDDP cells. In conclusion, SHP2 is a new cisplatin resistance-related phosphatase in lung cancer, which inhibits apoptosis by activating the Ras/PI3K/Akt1/survivin signaling pathway.

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“…Systematic review and meta-analysis have demonstrated that drug-induced apoptosis contribute to the inhibition of tumor cell growth and aggressiveness ( 23 ). In addition, it has been previously reported that Calotropin extracted from Asclepias curassavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells ( 11 ). In the present study, the efficacy of Calotropin on the inhibition of growth and aggressiveness of NSCLC cells was investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor apoptosis is a hallmark in the pathogenesis and treatment of patients with cancer ( 10 ). Calotropin is an active compound isolated from Asclepias curasavica L., which exerts strong inhibitory effects on cisplatin-induced resistance in NSCLC cells ( 11 ). A previous report has also revealed that Calotropin could inhibit the Wnt signaling pathway by increasing casein kinase 1a activity in colon cancer cells ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…A previous report has also revealed that Calotropin could inhibit the Wnt signaling pathway by increasing casein kinase 1a activity in colon cancer cells ( 12 ). A molecular mechanism study revealed that Calotropin regulated the apoptosis of tumor cells by inducing cell cycle arrest at the G2/M phase through decreasing the expression levels of cyclins, cyclin dependent kinase (CDK)-1 and CDK2 ( 11 ). In addition, cytotoxicity assays have indicated that Calotropin promoted caspase activation by downregulating the expression levels of anti-apoptotic proteins in K562 cells ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Calotropin regulates the apoptosis of non‑small cell cancer by regulating the cytotoxic T‑lymphocyte associated antigen 4‑mediated TGF‑β/ERK signaling pathway

2018

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Non-small-cell lung cancer (NSCLC) is one of the most common malignancies that is responsible for a high level of cancer-associated mortalities worldwide. Previous evidence has shown that Calotropin is an upstream activator of protein kinase B, which can further inhibit the growth and promote the apoptosis of NSCLC cells. In the present study, the efficacy of Calotropin on growth, aggressiveness and apoptosis of NSCLC cells was investigated, as well as the potential underlying mechanism. The results demonstrated that Calotropin inhibited H358 cell growth, migration and invasion. Flow cytometry assay showed that Calotropin promoted the apoptosis of H358 cells in vitro. Western blot analysis demonstrated that Calotropin inhibited fibronectin (FN), Vimentin (VIM) and E-cadherin (Eca) protein expression levels in H358 cells in vitro. In addition, Calotropin treatment upregulated pro-apoptosis gene expression, including caspase-3, caspase-8 and apoptotic protease activating factor-1, and downregulated anti-apoptosis gene expression, including P53, B-cell lymphoma (Bcl) 2 and Bcl-2-like protein 2 in H358 cells. The results also revealed that the expression levels of cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) were decreased by Calotropin treatment in H358 cells. Analyses of the underlying mechanism indicated that Calotropin inhibited transforming growth factor-β (TGF-β) and extracellular signal-regulated kinase (ERK) expression. Overexpression of CTLA-4 inhibited Calotropin-mediated downregulation of TGF-β and ERK expression in H358 cells. In vivo assay revealed that Calotropin administration significantly inhibited tumor growth and prolonged animal survival over the 120-day observation period. Immunohistochemistry demonstrated that the number of apoptotic cells increased and the expression levels of CTLA-4 were decreased in the Calotropin-treated tumor group when compared with control. In addition, the expression levels of TGF-β and ERK were downregulated in the Calotropin-treated tumor group compared with control. In conclusion, the results of the present study indicated that Calotropin administration regulated NSCLC apoptosis by downregulating the CTLA-4-mediated TGF-β/ERK signaling pathway, suggesting that Calotropin may be a potential anti-cancer agent for the treatment of NSCLC.

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Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells

Cited by 15 publications

References 26 publications

Anti-Tumor Effects of Atractylenolide-I on Human Ovarian Cancer Cells

Anti-Tumor Effects of Atractylenolide-I on Human Ovarian Cancer Cells

Src homology phosphotyrosyl phosphatase 2 mediates cisplatin-related drug resistance by inhibiting apoptosis and activating the Ras/PI3K/Akt1/survivin pathway in lung cancer cells

Calotropin regulates the apoptosis of non‑small cell cancer by regulating the cytotoxic T‑lymphocyte associated antigen 4‑mediated TGF‑β/ERK signaling pathway

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