Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin

Ortiz, T.; Burguillos, Miguel Ángel; López-Lluch, Guillermo; Navas, Plácido; Herrador, M.; González, I.; Piñero, J.

doi:10.1007/s00411-008-0188-6

Cited by 13 publications

(5 citation statements)

References 29 publications

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“…Wortmannin has been reported to synergistically enhance chemoradiotherapy with cisplatin or X-rays and reverse platinum and radio resistance in ovarian and bladder cancer models [53,54]. Our results indicated that the combination of TSE1 and wortmannin might be effective therapies for ovarian cancer.…”

Section: Discussionmentioning

confidence: 55%

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

Tong

Ren

et al. 2021

Molecules

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Novel therapeutic strategies for ovarian cancer treatment are in critical need due to the chemoresistance and adverse side effects of platinum-based chemotherapy. Theasaponin E1 (TSE1) is an oleanane-type saponin from Camellia sinensis seeds. Its apoptosis-inducing, cell cycle arresting and antiangiogenesis activities against platinum-resistant ovarian cancer cells were elucidated in vitro and using the chicken chorioallantoic membrane (CAM) assay. The results showed that TSE1 had more potent cell growth inhibitory effects on ovarian cancer OVCAR-3 and A2780/CP70 cells than cisplatin and was lower in cytotoxicity to normal ovarian IOSE-364 cells. TSE1 significantly induced OVCAR-3 cell apoptosis via the intrinsic and extrinsic apoptotic pathways, slightly arresting cell cycle at the G2/M phase, and obviously inhibited OVCAR-3 cell migration and angiogenesis with reducing the protein secretion and expression of vascular endothelial growth factor (VEGF). Western bolt assay showed that Serine/threonine Kinase (Akt) signaling related proteins including Ataxia telangiectasia mutated kinase (ATM), Phosphatase and tensin homolog (PTEN), Akt, Mammalian target of rapamycin (mTOR), Ribosome S6 protein kinase (p70S6K) and e IF4E-binding protein 1(4E-BP1) were regulated, and Hypoxia inducible factor-1α (HIF-1α) protein expression was decreased by TSE1 in OVCAR-3 cells. Moreover, TSE1 treatment potently downregulated protein expression of the Notch ligands including Delta-like protein 4 (Dll4) and Jagged1, and reduced the protein level of the intracellular domain (NICD) of Notch1. Combination treatment of TSE1 with the Notch1 signaling inhibitor tert-butyl (2S)-2-[[(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-2-phenylacetate (DAPT), or the Akt signaling inhibitor wortmannin, showed a stronger inhibition toward HIF-1α activation compared with single compound treatment. Taken together, TSE1 might be a potential candidate compound for improving platinum-resistant ovarian cancer treatment via Dll4/Jagged1-Notch1-Akt-HIF-1α axis.

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Section: Discussionmentioning

confidence: 55%

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

Tong

Ren

et al. 2021

Molecules

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“…DNAPKcs is a member of a subfamily of proteins containing the phosphatidylinositol (PI)-3 kinase domain, which could be inhibited by wortmannin. Ortiz et al (11) have reported that WM-dependent radiosensitization in RT112 radioresistant bladder tumor cells is a direct consequence of the inhibition of DNA-PK, resulting in the inhibition of DSB repair, suggesting that the expression level of DNA-PKcs in human tumor cells may be a good predictor for the success of DNAPKcs inhibitors when used as radiosensitizers. In vivo assays revealed that wortmannin, in combination with radiation therapy, may have potential benefits in cancer treatment for C3H/HeJ hepatocarcinoma (13).…”

Section: Discussionmentioning

confidence: 99%

“…Wortmannin is a widely used inhibitor of PI3 kinases (10). Wortmannin has been reported to have radiosensitization effects in RT112 bladder tumor cells (11) and BT-474 cells breast cancer cells (12) in vitro, and C3H/HeJ hepatocarcinoma (13) in vivo. For NSCLC cells, Sak et al (14) reported that the inhibition of DNA-dependent protein kinase activity with antisense-oligodeoxynucleotide (As-ODN) or wortmannin led to marked inhibition of DNA double strand breaks (DSBs) rejoining and radiosensitization of ONCOLOGY REPORTS 24: 1683-1689, 2010 Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation TAO In the current study, we investigated the effects of wortmannin on the response to Á-irradiation in NSCLC cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation

Zhang

Cui²,

Zhang³

et al. 2010

Oncol Rep

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Abstract. Non-small cell lung cancer (NSCLC) cells are relatively resistant to ionizing radiation (IR). The phosphatidylinositol 3 (PI3) kinases are members of a family of lipid kinases that mediate cellular functions, including cell growth, proliferation and DNA repair, which may contribute to radioresistance. We studied whether inhibition of PI3 kinases could increase the response of NSCLC cells to Á-irradiation. The results showed that pretreatment of PI3 kinase inhibitor wortmannin dose-dependently radiosensitized NSCLC A549 and H1650 cells by inhibiting colony formation, which was due to enhanced G2/M arrest and apoptosis by wortmannin. The accelerated apoptosis was accompanied by increased loss of mitochondrial membrane potential (MMP) and cytochrome c release to the cytoplasm. In addition, wortmannin pretreatment significantly increased caspase-3 activation, which was associated with the repression of X-linked inhibitor of apoptosis protein (XIAP). The radiosensitizing effect of wortmannin was correlated with the inhibition of phosphorylated PKB/Akt level. Furthermore, wortmannin down-regulated the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) which is involved in DNA double stand break (DSB) repair, as a result, leading to the inhibition of DSBs rejoining, as indicated by increased level of Á-H2AX at 24 h after IR. Taken together, our results demonstrate that wortmannin acts as a powerful radiosensitizer in NSCLC cells by inhibiting PI3K/Akt survival signaling and DNA repair protein DNA-PKcs, suggesting that PI3 kinase inhibitors may represent a novel strategy for overcoming resistance to IR-induced apoptosis in NSCLC cells.

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“…Mirzayans et al (29) have shown that inhibition of DSB rejoining by wortmannin may be an important contributor to its radiosensitizing effect in A549 cells. Ortiz et al (30) have reported that the radiosensitizing effect of wortmannin on RT112 bladder tumor cells is a direct consequence of the inhibition of DNA-PK, resulting in the inhibition of DSB repair. Wortmannin also inhibits ATM, which is activated in response to DSBs and functions upstream in the p53/p21…”

Section: Discussionmentioning

confidence: 99%

Replication-dependent γ-H2AX formation is involved in docetaxel-induced apoptosis in NSCLC A549 cells

Zhang

Zhang²,

Qu³

et al. 2010

Oncol Rep

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Abstract. Docetaxel is a member of the taxane antimicrotubule class of chemotherapeutic agents, which are currently widely used in clinical cancer therapy. However, the anti-tumor mechanisms of docetaxel are not fully understood. Herein we show that docetaxel induces dosedependent apoptosis in non-small cell lung cancer A549 cells, as detected by Annexin-V positive cells and PARP cleavage, which is via mitochondrial pathway and dependent on caspase-3 activation. Our study on the mechanisms confirms that docetaxel induces dose-dependent accumulation of cells in M phase and acetylation of ·-tubulin, marker of tubulin stablization. Furthermore, docetaxel induces replication-dependent Á-H2AX formation which plays a crucial role in docetaxel-triggered apoptosis. The DNA polymerase inhibitor aphidicolin dose-dependently prevents docetaxel-induced Á-H2AX formation, as well as apoptosis. Notably, 0.6 μM APC almost completely blocked docetaxelinduced Á-H2AX formation and apoptosis. In addition, wortmannin pretreatment caused elevated Á-H2AX level, which was accompanied with increased apoptosis. This effect was due to the inhibition of DNA repair process by wortmannin, as down regulation of p21Waf1/Cip1 and DNA repair proteins such as Ku70, Ku80, DNA-PKcs and Rad50, were detected. These data show, for the first time, that the induction of apoptosis by docetaxel requires DNA replication, and replication-mediated DSBs are critical triggers of docetaxel-induced apoptosis.

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Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin

Cited by 13 publications

References 29 publications

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation

Replication-dependent γ-H2AX formation is involved in docetaxel-induced apoptosis in NSCLC A549 cells

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