Abstract
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.
Highlights
Idelalisib, known as CAL-101 and GS-1101, is the first-in class phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitor, a cytoplasmic tyrosine kinase involved in a number of signaling pathways within B-cells [1]
We found that idelalisib treatment induces p53 upregulated modulator of apoptosis (PUMA) in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3β (GSK3β) activation
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 have important implications for it clinical applications
Summary
Idelalisib, known as CAL-101 and GS-1101, is the first-in class phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitor, a cytoplasmic tyrosine kinase involved in a number of signaling pathways within B-cells [1]. Idelalisib is approved as a single agent or combined with rituximab (Rituxan) to treat patients with follicular lymphoma, small lymphocytic lymphoma, and relapsed chronic lymphocytic leukemia (CLL) [2,3,4]. PUMA is a critical mediator of p53-dependent and p53-independent apoptosis in a variety of cancer cell and mice [7, 8]. DNA damage agents such as γ-irradiation, common chemotherapeutic drugs such as 5-fluorouracil (5-FU), induce p53 mediated PUMA induction and apoptosis [9]. PUMA induces apoptosis through interact with anti-apoptotic Bcl-2 family members such as Bcl-XL/Bcl, which activates the pro-apoptotic members Bax/Bak, resulting in mitochondrial dysfunction and activation of the caspase cascade [6, 15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
