IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines

Refolo, Maria Grazia; D’Alessandro, Rosalba; Lippolis, Catia; Carella, Nicola; Cavallini, A; Messa, Caterina; Carr, Brian I.

doi:10.18632/oncotarget.21403

Cited by 22 publications

(22 citation statements)

References 31 publications

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“…IGF-1R is a transmembrane protein with tyrosine kinase activity belonging to the insulin receptor family [34][35][36]. Up-regulation of IGF-1R has been observed in several cancers, including HCC and renal cell carcinoma [37,38]. It has been reported that IGF-1R interacted with the ligand IGF-1 and stimulated PI3K/AKT signaling pathway [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most common cancers globally. An increasing body of evidence has demonstrated the critical function of microRNAs (miRNAs) in the initiation and progression of human cancers. Here, we showed that miR-505 was down-regulated in HCC tissues and cell lines. Reduced expression of miR-505 was significantly correlated with the worse prognosis of HCC patients. Overexpression of miR-505 suppressed the proliferation, colony formation and induced apoptosis of both HepG2 and Huh7 cells. Further mechanism study uncovered that miR-505 bound the 3′-untranslated region (3′-UTR) of the insulin growth factor receptor (IGF-1R) and inhibited the expression of IGF-1R in HCC cells. The down-regulation of IGF-1R by miR-505 further suppressed the phosphorylation of AKT at the amino acid S473. Consistently, the abundance of glucose transporter (GLUT) 1 (GLUT1) was reduced with the overexpression of miR-505. Down-regulation of GLUT1 by miR-505 consequently attenuated the glucose uptake, lactate production and ATP generation of HCC cells. Collectively, our results demonstrated the tumor suppressive function of miR-505 possibly via inhibiting the glycolysis of HCC cells. These findings suggested miR-505 as an interesting target for designing anti-cancer strategy in HCC.

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Section: Discussionmentioning

confidence: 99%

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

et al. 2019

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“…Our previous studies have aimed to improve the actions of systemic drugs and reduce their toxicity, through methods such as targeting parallel pathways or treating in combination with natural compounds [ 19 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…With regard to human hepatocarcinoma (HCC), there is evidence showing an enhancement of the 5′-fluorouracil effect on HCC cell lines by CGA treatment, and more recently, Yan et al reported that CGA acts as an effective chemopreventive agent against HCC in both in vitro and in vivo experiments [ 17 , 18 ]. Our previous studies suggested that targeting parallel pathways or combining treatments based on natural compounds could improve the actions of systemic drugs and reduce their toxicity [ 19 ]. Although treatment with the multikinase inhibitor Regorafenib in patients who had HCC progression after Sorafenib failure provided a significant improvement in overall survival, drug toxicity, resistance and subsequent disease relapse are still a problem in HCC management.…”

Section: Introductionmentioning

confidence: 99%

Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells

Refolo

Lippolis

Carella

et al. 2018

IJMS

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Chlorogenic acid (CGA) is a polyphenol present in many human dietary foods. Several studies indicated a beneficial role of CGA in the prevention of cancer and an enhancement of chemotherapy when combined with CGA in the treatment of human hepatocarcinoma (HCC). Drug toxicity, resistance and subsequent disease progression represent a problem in HCC management, although treatment with the multikinase inhibitor Regorafenib improved overall survival. This study focused on the evaluation of the effects of combined treatment using both low Regorafenib concentrations and CGA as natural compound in HCC cells. The analysis of cell proliferation by Ki67 staining and cell cycle progression showed that CGA enhanced Regorafenib-mediated cell growth inhibition. Moreover, CGA potentiated the apoptotic effect of Regorafenib by the activation of the pro-apoptotic Annexin V, Bax and Caspase 3/7 and the inhibition of anti-apoptotic Bcl2 and Bcl-xL. Combined treatments were also effective in inhibiting cell motility. The mechanisms underlying the positive effects of combining CGA and Regorafenib were also addressed and an increased inhibition of MAPK (mitogen-activated protein kinase)and PI3K/Akt/mTORC (phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling was observed. Overall, these data demonstrated that co-treatment with Regorafenib and CGA enhanced Regorafenib action, reducing its cytotoxicity in HCC cells. In conclusion, this drug combination could be considered as a safe and more effective approach in HCC therapy.

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“…Several VKDPs are involved in tumorigenesis [71,84,85] (Table 3). Vitamin K2 administration in vivo inhibits the cellular proliferation of several cancers [96,97]. This led to a number of studies investigating the role of vitamin K intake and supplementation in preventing cancer development, progression and recurrence.…”

Section: Vitamin K In Cancermentioning

confidence: 99%

Vitamin K effects in human health: new insights beyond bone and cardiovascular health

et al. 2019

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Vitamin K is a cofactor for the function of the enzyme γ-glutamyl carboxylase, necessary for the activation of multiple vitamin K dependent-proteins. Vitamin K dependent-proteins (VKDPs) have important roles in bone health, vascular health, metabolism, reproduction as well as in cancer progression. Vitamin K deficiency is common in different conditions, including kidney disease, and it may influence the activity of VKDPs. This review discusses vitamin K status in human health and the physiologic and pathologic roles of VKDPs, beyond the established effects in skeletal and cardiovascular health.

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IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines

Cited by 22 publications

References 31 publications

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells

Vitamin K effects in human health: new insights beyond bone and cardiovascular health

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