idelalisib and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

Despite an old history behind the identification of the leading role of c-Myc in leukemogenesis, the road to constructing a therapeutic perspective for this molecule in acute lymphoblastic leukemia (ALL) is yet mesmerizing. This study was designed to provide a better outlook for the anticancer property of 10058-F4, an appealing inhibitor of c-Myc, in pre-B ALL cell lines either in the context of monotherapy or in combination with chemotherapeutic drugs. Our results declared that abrogation of c-Myc decreased the proliferative capacity of pre-B ALL-derived cells through halting the transition of the cells from G1 phase, and reducing the replicative potential of both REH and Nalm-6 cells, at least partly, through c-Myc-mediated suppression of human telomerase reverse transcriptase. Moreover, 10058-F4 potently induced a caspase-3-dependent apoptosis in pre-B ALL cells via shifting the balance between pro- and anti-apoptotic target genes. Although the inhibition of PI3Kδ using Idelalisib upregulated the messenger RNA expression of autophagy-related genes in 10058-F4-treated cells, treatment with autophagy inhibitor chloroquine decreased viability of the cells, either as a single agent or in combination with Idelalisib and/or 10058-F4; suggesting that the activation of autophagy in pre-B ALL cells could blunt apoptotic events and attenuate anticancer effect of both c-Myc and PI3K inhibitors. Finally, the results of our synergistic experiments delineated that 10058-F4 produced a synergistic effect with vincristine and provided an enhanced therapeutic efficacy in ALL cells, highlighting that c-Myc oncoprotein could be a bona fide target for the treatment of ALL.

Topics: Apoptosis; Autophagy; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; G1 Phase; Humans; NIMA-Interacting Peptidylprolyl Isomerase; Phosphatidylinositol 3-Kinases; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-myc; Purines; Quinazolinones; Telomerase; Thiazoles; Vincristine

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Doxorubicin; Drug Synergism; Enzyme Inhibitors; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Purines; Quinazolinones