PI3K-δ inhibition using CAL-101 exerts apoptotic effects and increases doxorubicin-induced cell death in pre-B-acute lymphoblastic leukemia cells.

Abstract

The frequency of dysregulated PI3K in acute lymphoblastic leukemia (ALL) coupled with the critical role of this signaling pathway in the acquisition of chemoresistant phenotype lend compelling weight to the application of PI3K inhibitors for the treatment of ALL. In this study, we found that abrogation of the PI3K pathway using CAL-101, a selective inhibitor of PI3K p110-δ, exerts a cytotoxic effect against Nalm-6 pre-B-ALL cells. Our results showed that the growth-suppressive effect is mediated, at least partially, by G1 arrest as a result of upregulated p21. CAL-101 also leads to induction of caspase-dependent apoptosis probably through reactive oxygen species-dependent upregulation of FOXO3a and subsequent induction of the proapoptotic target genes of p53. In conclusion, this study highlighted the potent efficacy of CAL-101 as either a single agent or in combination with doxorubicin in Nalm-6 cells; however, further investigation is needed to provide valuable clues to add this inhibitor for the treatment of ALL.

• Authors: Ava Safaroghli-Azar, Davood Bashash, Parisa Sadreazami, Majid Momeny, Seyed H Ghaffari
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 28 Issue 4 Pg. 436-445 (04 2017) ISSN: 1473-5741 [Electronic] England
• PMID: 28125433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Purines
• Quinazolinones
• Doxorubicin
• Class I Phosphatidylinositol 3-Kinases
• idelalisib

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, metabolism)
• Doxorubicin (administration & dosage, pharmacology)
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Humans
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, enzymology, pathology)
• Purines (administration & dosage, pharmacology)
• Quinazolinones (administration & dosage, pharmacology)