Abstract
Hepatocellular carcinoma (HCC) has increasing worldwide incidence but when unresectable lacks curative options. Treatment with a kinase inhibitor Sorafenib (Sf), while initially effective, results in only short increases in patient survival, thus there is a need for improved treatment regimens. Numerous treatment regimens have been explored wherein Sf is combined with other agents, such as non-toxic botanicals like Curcumin or Silibinin. Recently, we have shown that carnosic acid (CA), a component of the food preservative Rosemary Extract, can markedly enhance the cytotoxic actions of Sf in several cell lines derived from HCC, but not in the cell line Hu1545 derived from normal hepatocytes. CA has been shown to enhance Sf-induced cell death in the neoplastic cell lines, principally due to the composite of increased apoptosis and cytotoxic autophagy. In the present study we focused on the mechanisms that underlie the reduced proliferation and survival of HCC cells when CA is added to Sf and how this relates to the increase in Sf-induced DNA damage as well as to the elevation of cytoplasmic levels of reactive oxygen species (ROS). Importantly, the elevation of ROS levels induced by Sf was increased by adding CA. We found that CA enhanced Sf-induced prolongation of cell cycle, and the overall decrease in cell growth was associated with reduced activation of both STAT3 transcription factor (TF) and extracellular signal-regulated protein kinase (Erk)1/2. Our data suggest that a regimen incorporating CA, an inexpensive and non-toxic food additive, in the treatment of advanced HCC merits clinical evaluation.
Highlights
Hepatocellular carcinoma (HCC) has worldwide incidence but the advanced cases have few effective curative options
In the present study of Sf-treated HCC cells we focused on the mechanisms that underlie the reduced cell proliferation when carnosic acid (CA) is added to Sf and how this relates to the Sf-induced reactive oxygen species (ROS) generation, DNA damage, cell proliferation, and cell survival
We found that CA further increases DNA damage and the cell cycle block initiated by Sf, which correlates with ROS generation, reduced cell proliferation and cell survival, as well as the activation of the transcription factor (TF) STAT3, and of the proliferation-regulatory kinase extracellular signal-regulated protein kinase (ERK1/2)
Summary
Hepatocellular carcinoma (HCC) has worldwide incidence but the advanced cases have few effective curative options. Attempts to improve its prognosis have included the introduction of several multikinase inhibitors into clinical practice for therapy of advanced HCC, but until recently, sorafenib (Sf) was one of the most often used FDA approved systemic drugs for its treatment [1]. Improved patient outcomes were reported in randomized Phase III trials with regorafenib [4] and ramucirumab [5] as second line treatment after Sf alone failed to halt disease progression. Both clinical practice and laboratory studies have mainly focused on Sf, www.oncotarget.com originally developed as a Raf kinase inhibitor known as BAY 43-9006, and marketed as Nexavar (eg [6]). The enhanced cell death in the neoplastic cell lines was shown to be principally due to increased apoptosis and cytotoxic autophagy [13]
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