idelalisib and Colonic-Neoplasms

Idelalisib, a PI3K inhibitor, specifically targeting p110δ, has been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. However, the mechanisms of action of idelalisib in colon cancer cells are not well understood. We investigated how idelalisib suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. In this study, we found that idelalisib treatment induces PUMA in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3β (GSK3β) activation. PUMA is necessary for idelalisib-induced apoptosis in colon cancer cells. Idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and antitumor effect of idelalisib in xenograft model. These results demonstrate a critical role of PUMA in mediating the anticancer effects of idelalisib in colon cancer cells and suggest that PUMA induction can be used as an indicator of idelalisib sensitivity, and also have important implications for it clinical applications.

Topics: Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Drug Synergism; eIF-2 Kinase; Fluorouracil; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; HCT116 Cells; HT29 Cells; Humans; Mice; Phenylurea Compounds; Proto-Oncogene Proteins; Purines; Pyridines; Quinazolinones; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays