mTOR inhibitor RAD001 (everolimus) induces apoptotic, not autophagic cell death, in human nasopharyngeal carcinoma cells

Cai, Yuchen; Xia, Qing; Su, Quanguan; Luo, Rongzhen; Sun, Yulin; Shi, Yinghuan; Jiang, Wenqi

doi:10.3892/ijmm.2013.1282

Cited by 23 publications

(16 citation statements)

References 36 publications

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“…The results of this study showed that everolimus treatment decreased the expression of Ki-67, whereas the expression of caspase-3 was increased, indicating that everolimus may exert its anti-tumor effects by inducing apoptosis of tumor cells. These findings were consistent with those of a previous study showing that everolimus induces apoptosis in human nasopharyngeal carcinoma cells (Cai et al, 2013).…”

Section: Discussionsupporting

confidence: 93%

Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors

Zhang

Cheng

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Tumors, especially neuroendocrine tumors (NETs), can cause adverse effects on human health. The expression and significance of Ki-67 and caspase-3 in NET remain to be further explored. Everolimus is an important drug used for the treatment of NETs. In this study, we aimed to investigate whether everolimus exerts anti-tumor effects by suppressing the expression of Ki-67 and caspase-3 in NET. Tumor (different developmental stages) and adjacent tissues were collected from patients with NET. The expression of Ki-67 and caspase-3 were detected in 244 paraffin sections of NET using immunohistochemistry. RT-PCR and western blot were used to detect the expression of Ki-67 and caspase-3 at mRNA and protein levels, respectively. The patients (N = 244) were randomly divided into everolimus-intervention and control groups. RT-PCR and western blot were used to measure the expression changes of Ki-67 and caspase-3 before and after everolimus treatment. The rates of Ki-67 expression in NET grades 1-6 were 14.2, 22.1, 37.5, 59.9, 69.9, and 77.8%, respectively. The difference between the groups was significant. The rates of caspase-3 expression in NET grades 1-6 were 28.6, 33.3, 31.3, 60.0, 80.0, and 88.9%, respectively, and the difference between groups was significant. Moreover, the expression of Ki-67 and caspase-3 showed a significant negative correlation. The expression of Ki-67 decreased while that of caspase-3 increased after everolimus treatment. In conclusion, the decrease in Ki-67 expression and increase in caspase-3 expression after everolimus treatment indicated that everolimus exerted its anti-cancer effect by regulating the expression of Ki-67 and caspase-3.

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Section: Discussionsupporting

confidence: 93%

Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors

Zhang

Cheng

et al. 2017

Genet. Mol. Res.

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“…Since HSP70 is known to stabilize PARP [ 55 ], loss of HSP70-mediated stability offers an explanation for the everolimus induced PARP cleavage seen in this study. While there have been reports of autophagic and apoptotic cell death in leukemia [ 19 ] and nasopharyngeal carcinoma cells [ 56 ], everolimus is not known to induce cell death in breast cancer cells on its own [ 19 , 56 ]. To our knowledge, everolimus induced cell death in breast cancer has only been observed in aromatase expressing MCF-7/Aro cells when combined with letrozole [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

et al. 2016

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BackgroundmTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells.MethodsIn this study we utilized two AI-resistant breast cancer cell lines, MCF-7:5C and MCF-7:2A, which were clonally derived from estrogen receptor positive (ER+) MCF-7 breast cancer cells following long-term estrogen deprivation. Cell viability assay, colony formation assay, cell cycle analysis and soft agar anchorage-independent growth assay were used to determine the efficacy of everolimus in inhibiting the proliferation and tumor forming potential of MCF-7, MCF-7:5C, MCF-7:2A and MCF10A cells. Confocal microscopy and transmission electron microscopy were used to evaluate LC3-II production and autophagosome formation, while ERE-luciferase reporter, Western blot, and RT-PCR analyses were used to assess ER expression and transcriptional activity.ResultsEverolimus inhibited the proliferation of MCF-7:5C and MCF-7:2A cells with relatively equal efficiency to parental MCF-7 breast cancer cells. The inhibitory effect of everolimus was due to G1 arrest as a result of downregulation of cyclin D1 and p21. Everolimus also dramatically reduced estrogen receptor (ER) expression (mRNA and protein) and transcriptional activity in addition to the ER chaperone, heat shock protein 90 protein (HSP90). Everolimus restored 4-hydroxy-tamoxifen (4OHT) sensitivity in MCF-7:5C cells and enhanced 4OHT sensitivity in MCF-7 and MCF-7:2A cells. Notably, we found that autophagy is one method of everolimus insensitivity in MCF-7 breast cancer cell lines.ConclusionThis study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as part of combination therapy for AI-resistant breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2490-z) contains supplementary material, which is available to authorized users.

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“…no. 04744926001; Roche diagnostics GmbH, Mannheim, Germany) (31). Following PdT treatment, cells incubated with 1% Τriton X-100 served as a control for maximum LDH release.…”

Section: Methodsmentioning

confidence: 99%

Novel zinc‑ and silicon‑phthalocyanines as photosensitizers for photodynamic therapy of cholangiocarcinoma

et al. 2018

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Photodynamic therapy (PDT) has emerged as an effective and minimally invasive cancer treatment modality. In the present study, two novel phthalocyanines, tetra‑triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) and dihydroxy‑2,9(10),16(17),23(24)‑tetrakis(4,7,10‑trioxaundecan‑1‑sulfonyl) silicon phthalocyanine (Pc32), were investigated as photosensitizers (PS) for PDT of cholangiocarcinoma (CC). ZnPc showed a pronounced dose‑dependent and predominantly cytoplasmic accumulation in EGI‑1 and TFK‑1 CC cell lines. Pc32 also accumulated in the CC cells, but this was less pronounced. Without photoactivation, the PS did not exhibit any antiproliferative or cytotoxic effects. Upon photoactivation, ZnPc induced the formation of reactive oxygen species (ROS) and immediate phototoxicity, leading to a dose‑dependent decrease in cell proliferation, and an induction of mitochondria‑driven apoptosis and cell cycle arrest of EGI‑1 and TFK‑1 cells. Although photoactivated Pc32 also induced ROS formation in the two cell lines, the extent was less marked, compared with that induced by ZnPc‑PDT, and pronounced antipoliferative effects occurred only in the less differentiated EGI‑1 cells, whereas the more differentiated TFK‑1 cells did not show sustained growth inhibition upon Pc32‑PDT induction. In vivo examinations on the antiangiogenic potency of the novel PS were performed using chorioallantoic membrane (CAM) assays, which revealed reduced angiogenic sprouting with a concomitant increase in nonperfused regions and degeneration of the vascular network of the CAM following induction with ZnPc‑PDT only. The study demonstrated the pronounced antiproliferative and antiangiogenic potency of ZnPc as a novel PS for PDT, meriting further elucidation as a promising PS for the photodynamic treatment of CC.

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mTOR inhibitor RAD001 (everolimus) induces apoptotic, not autophagic cell death, in human nasopharyngeal carcinoma cells

Cited by 23 publications

References 36 publications

Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors

Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors

Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

Novel zinc‑ and silicon‑phthalocyanines as photosensitizers for photodynamic therapy of cholangiocarcinoma

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