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Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility.

ABSTRACT: Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell cycle analysis were assessed for cell proliferation and Annexin V and western blotting analysis relative to the expression of cleaved Caspase-3 and BID for cell apoptosis. In these experimental conditions cell growth and migration were potently inhibited and apoptosis induced even in HCC cells producing high alpha fetoprotein (AFP) levels (clinically worse prognosis). The combination also inhibited levels of the two HCC biomarkers, AFP and des gamma carboxy prothrombin (DCP). Additional inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced effects on AFP and DCP levels, cell growth inhibition and MAPK and PI3K/Akt signaling inhibition due to sorafenib/regorafenib combination. These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies.

SUBMITTER: D'Alessandro R

PROVIDER: S-EPMC6627995 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility.

D'Alessandro Rosalba R Refolo Maria Grazia MG Iacovazzi Palma Aurelia PA Pesole Pasqua Letizia PL Messa Caterina C Carr Brian Irving BI

Cancers 20190607 6

Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell c ...[more]

PMID: 31181647

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Project description:Background: Sorafenib is a standard drug used for advanced hepatocellular carcinoma but is often resistant and toxic. Its combination with epigallo-3-catechin gallate leads to reduced resistance and toxicity but an equally effective anti-angiogenic effect.Therefore, this study aims to assess the anti-angiogenic effect of standard-dose Sorafenib compared to the combination of low-dose Sorafenib and epigallo-3-catechin gallate. Methods: We conducted an animal study and double-blind, randomized controlled trials. A total of 25 male Wistar rats (7-weeks-old) were randomly divided into four groups, namely Sham (K), Control (O), a combination of low-dose Sorafenib and epigallo-3-catechin gallate group (X1), and standard-dose Sorafenib group (X2). All groups were injected with N-Nitrosodiethylamine 70 mg/kg body weight (BW) intraperitoneally for ten weeks, except the Sham group. After the development of hepatocellular carcinoma, X1 and X2 were treated for two weeks. Subsequently, liver tissues were examined for vascular endothelial growth factor (VEGF) level and microvascular density expression. Results: There was a significant difference (p=0.007) in the level of VEGF between group X1 (low dose Sorafenib + EGCG) and X2 (Standard dose Sorafenib). However, the differences in VEGF levels of group X1 and X2 compared to group O(Control) were significantly lower, with values p=0.000136 and p=0.019, respectively. The expression of microvascular density between groups X1 and X2 was not entirely different. Meanwhile, a significant difference (p<0.05) was discovered when both groups were compared with the control group. Conclusion: The combination of low-dose Sorafenib with epigallo-3-catechin gallate is superior in reducing the level of VEGF compared to standard-dose Sorafenib and is better than the control. Standard-dose Sorafenib and the combination of low-dose Sorafenib and epigallo-3-catechin gallate have similar effectivity in reducing the expression of microvascular density and could prevent resistance and lower toxicity effects.

Dataset Information

Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility.

Publications

Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility.

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