Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is a common and deadly cancer worldwide and is often refractory to chemotherapy due to the development of multidrug resistance. Lonafarnib is an orally active and potent non-peptidomimetic inhibitor of farnesyl transferase. Here, using in vitro HCC cell models, we demonstrated that lonafarnib inhibited tumor proliferation and reduced the activity of mitogen-activated protein kinases pathways. In addition, lonafarnib caused G1 to S phase arrest through the downregulation of Cyclin D1, CDK6 and SKP2, while it induced cellular apoptosis by promoting the cleavage and activation of Caspase-3 and PARP. When combined with doxorubicin and sorafenib, lonafarnib was able to increase the sensitivity of HCC cells to chemotherapy. Furthermore, we also constructed ABCB1-overexpressing HCC cells and found that lonafarnib decreased chemoresistance by inhibiting ABCB1-mediated drug efflux activity. These results suggest that lonafarnib may be a promising synergistic agent for improving the treatment of drug-resistant HCC.

The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells

“…Although their antitumor abilities have been demonstrated with many cancers [29], the effect on HCC has received less attention. Different from our previous study in which we identified the synergistic effect of lonafarnib and sorafenib to inhibit the growth of HCC cell lines SMMC-7721 and QGY-7703 [30], in this study, using both in vitro and in vivo models, we confirmed the cytotoxic effect of this combination on another HCC cell line HepG2. Both lonafarnib and sorafenib alone were able to inhibit cellular proliferation, colony formation and induced cell death in HepG2 cells, and concurrent treatment with these two agents markedly increased the therapeutic effect.…”

A SARS-CoV-2 cytopathicity dataset generated by high-content screening of a large drug repurposing collection

“…Dapivirine (IC 50 = 0.73 µM) is a non-nucleoside reverse transcriptase inhibitor developed for the treatment of HIV, which was recently shown to possess broad antiviral activity with micromolar IC 50 values against influenza viruses A and B in vitro 40 . The orally available farnesyl transferase inhibitor lonafarnib (IC 50 = 5.68 µM) has been considered as a treatment for renal carcinoma 41 and showed activity against hepatitis delta virus 42 . The moderately potent pre-clinical compound NSC319276 elevates intracellular Zn 2+ levels, thus modulating the folding of p53 43 .…”

Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection

“…This compound was selected, among others, after a virtual screening analysis against the SARS-CoV-2 viral protease Mpro(16) and, following additional confirmatory in-vitro and in-vivo studies, may be a viable candidate for further development. The orally available farnesyl transferase inhibitor ionafarnib (IC50 = 5.68 µM) has been studied in renal carcinoma(17) and has anti-viral activity in hepatitis D(18).The crystallization of SARS-CoV-2 spike protein complexed to Angiotensin-Converting Enzyme-2 (ACE2) [PDB code = 6M18](19), has shed new light on possible SARS-CoV-2 virus entry mechanisms modulating virus-host interactions. ACE2 is expressed in Caco-2, Calu-3 and Vero-6 cells on the apical membrane domains…”