The Eltrombopag antitumor effect on hepatocellular carcinoma

Abstract

Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia.

Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ

“…48,49 Chelation was also observed in vivo in AA patients treated with eltrombopag. 50 This effect has been proposed to account, in part, for the improved function of cells cultured with eltrombopag, its antiproliferative properties in acute myeloid leukemia 48,51 and hepatocellular carcinoma, 52 and the clinical hematopoietic benefits in subjects with AA [38][39][40] and myelodysplastic syndrome. 53 The iron-mobilizing effects were observed in human and rodent cells.…”

The preoperative alkaline phosphatase-to-platelet ratio index is an independent prognostic factor for hepatocellular carcinoma after hepatic resection

“…[14–16] In China, the vast majority (about 95%) of HCC patients have HBV infection and liver cirrhosis, and patients with liver cirrhosis, portal hypertension, hypersplenism, and low platelet and WBC levels develop HCC; on the other hand, due to liver damage, serum liver biochemistry enzyme indexes are increased—for example, ALP, AST, ALT, and γ-GT levels—primarily leading to an increased APPRI. Furthermore, platelets have been well established to play a key role in liver fibrosis, [17,18] cirrhosis, [19] tumor growth, and metastasis. [20–23] Thrombocytopenia exacerbates liver fibrosis.…”

“…[17] By contrast, increasing the platelet count suppresses hepatic fibrosis. [18] Other studies have also suggested that small HCCs usually arise in cirrhosis, often associated with thrombocytopenia. [19] We speculate that the level of APPRI may correlate with HCC progress, which would have important clinical application value.…”

Platelets in chronic liver disease, from bench to bedside

“…In fact, the cytostatic effect of eltrombopag seems to be mediated mainly by an alteration of iron metabolism in cancer cells. 104 Regarding patients with cholangiocarcinoma, only a few clinical studies based on the platelet-to-lymphocyte ratio indicate a possible increase in platelet counts related to poor prognosis and survival. 105 Therefore, in the context of liver cancer, a better comprehension of the cellular and molecular mechanisms underlying the interactions between platelets, cancer cells and immune cells is urgently required to validate the efficacy of a potential anti-platelet therapeutic approach.…”