Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

Fiore, Michele; D’Angelillo, Rolando Maria; Greco, Carlo; Fioroni, Iacopo; Ippolito, Edy; Santini, Daniele; Ramella, Sara

doi:10.1159/000488252

Cited by 7 publications

(7 citation statements)

References 46 publications

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“…As discussed earlier, the mechanism of action of several chemotherapeutic agents is through increased ROS production and elevated oxidative stress in cancer cells 12 . Sorafenib is a multikinase inhibitor, which can downregulate tumor proliferation and angiogenesis 21,22 . Sorafenib is currently being used in the treatment for metastatic RCC and other cancers 21–23 .…”

Section: Introductionmentioning

confidence: 99%

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Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1

et al. 2019

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Any imbalance between reactive oxygen species (ROS) generation and the anti-oxidant capacity lead to cellular oxidative stress. Many chemotherapeutic agents mediate their cytotoxic functions through the generation of ROS. c-Met, a receptor tyrosine kinase, is over-expressed in renal cancer and plays very crucial role(s) in its growth and survival. Here, we show that c-Met activation protected renal cancer cells from ROS, oxidative stress and cytotoxicity induced by the anti-cancer agent sorafenib (used for renal cancer treatment); and it markedly attenuated sorafenib-induced DNA damage. Activated c-Met promoted the anti-apoptotic proteins (Bcl-2 and Bcl-xL) and inhibited apoptotic cleaved caspase-3. We found that the cytoprotective function of c-Met against sorafenib-induced ROS generation and apoptosis was mediated primarily through the activation of anti-oxidant Nrf2-HO-1. c-Met promoted the nuclear localization of Nrf2 and hindered its binding with the inhibitory protein Keap1. Silencing of Nrf2 attenuated the protective action of c-Met against sorafenib-induced oxidative stress. To evaluate the physiological significance of our findings, in a tumor xenograft model, we observed that a combination treatment with pharmacological inhibitors of c-Met and it’s anti-oxidant downstream effecter HO-1 markedly reduced the growth of renal tumor in vivo; it increased the oxidative stress, DNA damage and apoptotic markers in the tumor xenografts, along with reduced tumor vessel density. Our observations indicate that the c-Met-Nrf2-HO-1 pathway plays a vital role in relieving ROS-mediated oxidative stress of renal tumors. Targeting this pathway can significantly increase the oxidative stress to promote apoptotic death of cancer cells.

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Section: Introductionmentioning

confidence: 99%

“…Sorafenib is a multikinase inhibitor, which can downregulate tumor proliferation and angiogenesis 21,22 . Sorafenib is currently being used in the treatment for metastatic RCC and other cancers 21–23 . Sorafenib is known to generate ROS and inhibit mitochondrial respiration along with the interruption of cellular glycolysis 23 .…”

Section: Introductionmentioning

confidence: 99%

Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1

et al. 2019

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“…To date, receptor tyrosine kinase (RTK) inhibitor family molecules have been used for the therapy of multiple cancers, including lung cancer [36], renal cancer [37], and cholangiocarcinoma [38]. Interestingly, our previous study found that the receptor tyrosine kinase (RTK) inhibitor brivanib downregulates the phosphorylation of FGFR1 and…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib, a Multityrosine Kinase Inhibitor of MET and VEGF Receptors Which Suppresses Mouse Laser-Induced Choroidal Neovascularization

Zhang

Zhu

Xie

et al. 2020

Journal of Ophthalmology

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Choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries and is particularly associated with age-related macular degeneration (AMD). Cabozantinib (CBZ) hinders the activation of multiple receptor tyrosine kinases involved in tumor angiogenesis, such as hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2). We aimed to investigate the role and mechanism of CBZ in a mouse laser-induced CNV model. In zebrafish embryos, CBZ perturbed intersegmental vessel (ISV) formation without obvious neurodevelopment impairment. In the mouse laser-induced CNV model, phosphorylated hepatocyte growth factor receptor (p-MET) and phosphorylated vascular endothelial growth factor receptor 2 (p-VEGFR2) were increased in the CNV region. CBZ intravitreal injection or oral gavage alleviated CNV leakage and the CNV lesion area without obvious intraocular toxicity, as well as disturbed the phosphorylation of MET and VEGFR2. Additionally, CBZ downregulated the expression of the hepatocyte growth factor (HGF) with no effect on the expression of the vascular endothelial growth factor (VEGF). CBZ downregulated HGF, p-MET, and p-VEGFR2 expressions in vitro, as well as inhibited the proliferation, migration, and tube formation of b-End3 cells. In summary, CBZ alleviates mouse CNV formation possibly via inhibiting the activation of MET and VEGFR2. The findings provide a novel potential therapy method for CNV patients.

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“…Many other molecules are being developed. Advances in metastatic RCC have markedly increased with such medications [1][2][3][4][5].…”

mentioning

confidence: 99%

“…Although RCC is a tumor that is resistant to conventional RT. In preclinical studies, RCC has been reported to show higher radio sensitivity when using a program subject to ablative, hypo fraction in RT [5][6][7]. There are currently no phase 2 and 3 studies evaluating this combination in the literature.…”

mentioning

confidence: 99%

Axitinib radiotherapy combination in rcc cancer

Cihan

2019

Glob J Urol

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In conclusion, metastatic RCC has been a prototype of targeted cancer therapies as a result of advances in molecular medicine. Axitinib and RT combination approaches, one of the targeted therapies, have been shown to increase radiosensitivity in preclinical studies. The evaluation of the treatment regimens and the results of the Axitinib and RT combination therapy for metastatic RCC cases with phase 2 and 3 studies will be important for the patient.

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Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

Cited by 7 publications

References 46 publications

Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1

Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1

Cabozantinib, a Multityrosine Kinase Inhibitor of MET and VEGF Receptors Which Suppresses Mouse Laser-Induced Choroidal Neovascularization

Axitinib radiotherapy combination in rcc cancer

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