Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells
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Xuening Wang1, Priya Gupta1, Yasmeen Jramne2, Michael Danilenko2, Dongfang Liu1,3 and George P. Studzinski1
1 Department of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
2 Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
3 Center for Immunity and Inflammation, New Jersey Medical School, Rutgers the State University of New Jersey, Newark, NJ 07103, USA
|George P. Studzinski,||email:||[email protected]|
Keywords: sorafenib; carnosic acid; ERK1/2; STAT3; hepatoma
Received: June 19, 2020 Accepted: July 07, 2020 Published: August 18, 2020
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.
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