Molecular analysis of sunitinib resistant renal cell carcinoma cells after sequential treatment with <scp>RAD</scp>001 (everolimus) or sorafenib

Juengel, Eva; Kim, Dana; Makarević, Jasmina; Reiter, Michael; Tsaur, Igor; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A.

doi:10.1111/jcmm.12471

Cited by 29 publications

(30 citation statements)

References 35 publications

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“…In terms of the RCC cell targeted activity of TKIs, it was shown that the short-term (24 h) application of sunitinib in renal cell carcinoma Caki-1 and KTC-26 cell lines induced cell growth inhibition, which was halted in the M and G 2 phases. The signs of anti-RCC cell toxicity became apparent when the cells were exposed to 10 µM of sunitinib; additionally, sorafenib caused a distinct downregulation of the tumor cell number at a dosage of ≥5 µM (63). However, when RCC cells were exposed to 1 µM sunitinib for 8 weeks (equivalent to a 1.3 treatment cycle) cdk1 and cdk2 were overexpressed, p27 was downregulated, and Akt, Rictor, and Raptor were activated (63).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer

et al. 2015

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This study was designed to analyze the impact of multi-targeted tyrosine kinase inhibitors on the cancer stem cell subpopulation in renal cell cancer. The second objective was to evaluate the effect of tumor growth inhibition related to a tumor niche factor - oxygen deprivation - as hypoxia develops along with the anti-angiogenic activity of tyrosine kinase inhibitors in renal tumors. Cells were treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, in 2D and 3D culture conditions. Cell proliferation along with drug toxicity were evaluated. It was shown that the proliferation rate of cancer stem cells was decreased by the tyrosine kinase inhibitors. The efficacy of the growth inhibition was limited by hypoxic conditions and 3D intratumoral cell-cell interactions. We conclude that understanding the complex molecular interaction feedback loops between differentiated cancer cells, cancer stem cells and the tumor microenvironment in 3D culture should aid the identification of novel treatment targets and to evalute the efficacy of renal cancer therapies. Cell-cell interaction may represent a critical microenvironmental factor regulating cancer stem cell self-renewal potential, enhancing the stem cell phenotype and limiting drug toxicity. At the same time the role of hypoxia in renal cancer stem cell biology is also significant.

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Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer

et al. 2015

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“…In contrast, Juengel et al [130] reported that everolimus resistance in vitro was characterized by elevated expression of Akt and S6K1, as well as cell-cycle-activating proteins CDK2 and cyclin A, which allowed for the subsequent increased number of G 2 /M-phase cells. In a follow-up study, they reported that everolimus evoked a strong response in sunitinib-resistant RCC cells by inducing cell growth delay in G 0 /G 1 and diminishing expression levels of p-Akt, p-raptor and p-rictor [131]. Everolimus also counteracted chronic sunitinib-induced CDK1 and CDK2 upregulation.…”

Section: Cellular Effects Of Everolimusmentioning

confidence: 95%

“…One strategy to overcome these limitations has been to test combinations of rapalogues with other known inhibitory agents. For example, both Juengel et al [131] and Larkin et al [132] demonstrated the potential of using everolimus as a second-line therapy following failure of first-line sunitinib treatment. Yao et al [206] showed improved efficacy of everolimus and octreotide combination to treat neuroendocrine tumours compared with everolimus alone.…”

Section: Future Research Directionsmentioning

confidence: 99%

Cellular and molecular effects of the mTOR inhibitor everolimus

2015

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mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.

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“…In light of the fact that renal carcinoma is one of the most deadly types of cancers, some candidates have been introduced to stop and/or limit the progression of the metastasis of this carcinoma, for example, sunitinib and pazopanib, drugs that are reported to be the inhibitors of tyrosine kinase (6,7). Indeed, these agents were found to be able to stop the growth of cancer cells but extensive research on these agents revealed that they are associated with drug resistance and they have various side-effects as well (8,9). Therefore, there is a need to introduce potent candidates that are originated from a natural source and are not destructive to the normal physiological condition of cells or tissue.…”

Section: Introductionmentioning

confidence: 99%

Thymoquinone induces apoptosis through downregulation of c-FLIP and Bcl-2 in renal carcinoma Caki cells

et al. 2016

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Renal carcinoma is a common and frequently fatal carcinoma occurring worldwide and death rates due to this carcinoma are increasing with time. In the present study, we investigated the potential of thymoquinone a natural compound to induce apoptosis in renal carcinoma Caki cells. Thymoquinone efficiently enhanced the apoptotic population of Caki cells in a dose-dependent manner. Moreover, thymoquinone-mediated apoptosis caused downregulation of c-FLIP and Bcl-2, the master regulators of the anti-apoptotic mechanism. However, we did not find any changes in mRNA expression level of c-FLIP, therefore; this regulation of c-FLIP was a result of post-translation modification by thymoquinone. In contrast, expression of the Bcl-2 protein was observed at both transcriptional and translational level. However, we also observed that thymoquinone enhanced the level of intracellular reactive oxygen species (ROS) in Caki cells, which resulted in reduction of mitochondrial membrane potential (MMP) and cytochrome c release into cytoplasm. Our results postulate that thymoquinone induces apoptosis through downregulating c-FLIP and Bcl-2 which can be utilized as a chemotherapeutic agent to treat renal carcinoma.

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Molecular analysis of sunitinib resistant renal cell carcinoma cells after sequential treatment with RAD001 (everolimus) or sorafenib

Cited by 29 publications

References 35 publications

Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer

Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer

Cellular and molecular effects of the mTOR inhibitor everolimus

Thymoquinone induces apoptosis through downregulation of c-FLIP and Bcl-2 in renal carcinoma Caki cells

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