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.
Highlights
Until recently sorafenib was the only FDA approved systemic drug for the treatment of advanced hepatocellular carcinoma (HCC) [1]
Within the last few years, a number of other tyrosine kinase inhibitors (TKIs) have been investigated and lenvatinib represents the first breakthrough for first line therapy (REFLECT trial) [2] after multiple other trial failures and it is currently FDA approved as a treatment for patients with metastatic HCC
We initially examined whether addition of regorafenib could enhance sorafenib-mediated growth inhibition
Summary
Until recently sorafenib was the only FDA approved systemic drug for the treatment of advanced hepatocellular carcinoma (HCC) [1]. Improvements in patient outcomes have been demonstrated in randomized Phase III trials with regorafenib [3] and ramucirumab [4] as second line treatments after disease progression on sorafenib. Patients may develop resistance to a given treatment by activating alternative signaling that bypass the inhibitory effect of a single agent. The aim of the present study was to investigate the effects on cell growth and motility of the combined treatment of low doses of sorafenib and regorafenib. The effects of ramucirumab and GSK1838705A were evaluated on two human HCC cell lines (PLC/PRF/5 and HepG2) characterized by different basal levels of AFP and DCP, in order to correlate the efficacy of specific drug treatments to the content of the two markers and possibly to detect changes in their expression following the treatments themselves
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