idelalisib and Liver-Neoplasms

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound

Topics: Carcinoma, Hepatocellular; Class I Phosphatidylinositol 3-Kinases; Humans; Indazoles; Liver Neoplasms; Protein Kinase Inhibitors

Idelalisib, a selective PI3Kδ inhibitor, has been approved by the FDA for chronic lymphocytic leukemia/small lymphocytic lymphoma treatment and for follicular lymphoma treatment when combined with rituximab. However, the mechanisms of effective action of idelalisib in hepatocellular carcinoma (HCC) remain unclear. In the current study, we aimed to investigate how idelalisib inhibits the growth of HCC cells and enhances the effects of other chemotherapeutic drugs. Our results show that idelalisib treatment promotes Bim induction in HCC via the FoxO3a pathway following PI3K/AKT inactivation. Moreover, our results show that Bim is required for idelalisib-mediated apoptosis in HCC. Idelalisib also synergizes with sorafenib or doxorubicin to induce significant apoptosis in HCC, and Bim is also necessary for the induction of apoptosis by cotreatment. Furthermore, a xenograft experiment reveals that the Bim deficiency abolishes apoptosis and antitumor effects of idelalisib in vivo. In summary, our results indicate a key role of Bim in mediating the antitumor effects of idelalisib in HCC. Our results also support the clinical significance of the drug.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Chromatin Immunoprecipitation; Female; Forkhead Box Protein O3; Gene Expression Regulation, Neoplastic; HEK293 Cells; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones

Class I phosphoinositide 3-kinase (PI3K) signaling is a major pathway in human cancer development and progression. Among the four PI3K isoforms, PI3Kα and PI3Kβ are ubiquitously expressed, whereas PI3Kγ and PI3Kδ are found primarily in leukocytes. Until now, PI3K targeting in solid tumors has focused on inhibiting PI3Kα-mediated and PI3Kβ-mediated cancer cell-intrinsic PI3K activity. The role of PI3Kδ in solid tumors is unknown. Here, we evaluated the effects of PI3Kδ using established hepatocellular carcinoma (HCC) cells, malignant hepatocytes derived from patients with advanced HCC, murine models, and HCC tissues using RNA sequencing, quantitative PCR, immunoblotting, immunofluorescence, microarray, liquid chromatography-tandem mass spectrometry, and kinase assay. We established a chemical carcinogenesis model of liver malignancy that reflects the malignant phenotype and the in vivo environment of advanced HCC. In this in vivo advanced HCC-mimic system using HCC cells treated with hydrogen peroxide (H

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Class I Phosphatidylinositol 3-Kinases; Drug Screening Assays, Antitumor; Humans; Hydrogen Peroxide; Liver Neoplasms; Mice; Molecular Targeted Therapy; Purines; Quinazolinones; Serpins; Telomerase

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Merkel Cell; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Liver; Liver Neoplasms; Neoplasm Staging; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Purines; Quinazolinones; Radiography; Radionuclide Imaging; Skin Neoplasms