pf-3084014 and Carcinoma--Hepatocellular

The γ-secretase complex is a key hydrolase for many type 1 transmembrane proteins. It is very important for activation of the Notch receptor and regulation of target-gene transcription. Abnormal activation and expression of the Notch pathway are closely related to the occurrence and development of many tumor types, including breast cancer and liver cancer. In this review, we elaborated on the basic situation of γ-secretase complex and the biological function and role of γ-secretase in APP and Notch signal pathway are described in detail. Subsequently, all currently known γ-secretase inhibitors and γ-secretase modulators are listed and their mechanism of action, value of IC

Topics: Amyloid Precursor Protein Secretases; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Oligopeptides; Protease Inhibitors; Receptors, Notch; Tetrahydronaphthalenes; Valine

Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma.

Topics: Antineoplastic Agents; Carcinogenesis; Carcinoma, Hepatocellular; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; Humans; Liver Neoplasms; Neoplasm Metastasis; Neoplastic Stem Cells; Receptor, Notch1; Spheroids, Cellular; STAT3 Transcription Factor; Tetrahydronaphthalenes; Valine