Synergistic Effects of PI3K Inhibition on Arsenic Trioxide Cytotoxicity in Acute Promyelocytic Leukemia Cells: A New Portrait of Idelalisib As an Adjuvant Therapy

Overview

Journal Indian J Hematol Blood Transfus

Specialty Hematology

Date 2023 Apr 3

PMID 37006983

Authors

Maryam Dadashi

Atieh Pourbagheri-Sigaroodi

Ali Anjam-Najmedini

Davood Bashash

Affiliations

Soon will be listed here.

Abstract

The advent of small-molecule inhibitors targeting the components of oncogenic signaling pathways has revolutionized cancer treatment, where the pharmacological approaches have gone from an era of non-specific chemotherapeutic drugs to the golden age of targeted therapies. In the present study, we evaluated the therapeutic value of an isoform-specific inhibitor of PI3K (Idelalisib) in potentiating the anti-leukemic effects of arsenic trioxide (ATO), an eminent drug used in the treatment of acute promyelocytic leukemia (APL). We found that the abrogation of the PI3K axis profoundly reinforced the anti-leukemic effects of the lower concentrations of ATO, as revealed by the superior reduction in the viability, cell number, and metabolic activity of APL-derived NB4 cells as compared to either agent alone. The cytotoxic effect of Idelalisib in combination with ATO was probably mediated through suppression of c-Myc that was coupled with the elevation in the intracellular level of reactive oxygen species and induction of caspase-3-dependent apoptosis. Notably, our results showed that the suppression of autophagy reinforced the ability of the drugs in eradicating the leukemic cells, suggesting that the compensatory activation of this system may probably overshadow the success of Idelalisib-plus-ATO in APL cells. All in all and given the significant efficacy of Idelalisib against NB4 cells, we proposed the application of this PI3K inhibitor as a foreseeable approach with a safe profile in the treatment of APL.

References

Evangelisti C, Evangelisti C, Chiarini F, Lonetti A, Buontempo F, Neri L . Autophagy in acute leukemias: a double-edged sword with important therapeutic implications. Biochim Biophys Acta. 2014; 1853(1):14-26. DOI: 10.1016/j.bbamcr.2014.09.023. View

Das R, Bhattacharya K, Sarkar S, Samanta S, Pal B, Mandal C . Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS-mediated activation of PTEN and p53/p73 in colon carcinoma. Apoptosis. 2013; 19(1):149-64. DOI: 10.1007/s10495-013-0907-6. View

Shiri Heris R, Safaroghli-Azar A, Yousefi A, Hamidpour M, Bashash D . Anti-leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c-Myc and autophagy on BKM120 cytotoxicity. Cell Biol Int. 2020; 44(5):1212-1223. DOI: 10.1002/cbin.11322. View

Tabellini G, Cappellini A, Tazzari P, Fala F, Billi A, Manzoli L . Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells. J Cell Physiol. 2004; 202(2):623-34. DOI: 10.1002/jcp.20153. View

Gewirtz D . Autophagy and senescence: a partnership in search of definition. Autophagy. 2013; 9(5):808-12. PMC: 3669198. DOI: 10.4161/auto.23922. View

Panda M, Biswal B . Cell signaling and cancer: a mechanistic insight into drug resistance. Mol Biol Rep. 2019; 46(5):5645-5659. DOI: 10.1007/s11033-019-04958-6. View

McCubrey J, Steelman L, Abrams S, Lee J, Chang F, Bertrand F . Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006; 46:249-79. DOI: 10.1016/j.advenzreg.2006.01.004. View

Billottet C, Banerjee L, Vanhaesebroeck B, Khwaja A . Inhibition of class I phosphoinositide 3-kinase activity impairs proliferation and triggers apoptosis in acute promyelocytic leukemia without affecting atra-induced differentiation. Cancer Res. 2009; 69(3):1027-36. DOI: 10.1158/0008-5472.CAN-08-2608. View

Nowak T, Januszkiewicz D, Zawada M, Pernak M, Lewandowski K, Rembowska J . Amplification of hTERT and hTERC genes in leukemic cells with high expression and activity of telomerase. Oncol Rep. 2006; 16(2):301-5. View

10.

Bashash D, Safaroghli-Azar A, Dadashi M, Safa M, Momeny M, Ghaffari S . Anti-tumor activity of PI3K-δ inhibitor in hematologic malignant cells: Shedding new light on resistance to Idelalisib. Int J Biochem Cell Biol. 2017; 85:149-158. DOI: 10.1016/j.biocel.2017.02.007. View

11.

Nguyen L, Sesay A, Mitchell B . Effect of CAL-101, a PI3Kδ inhibitor, on ribosomal rna synthesis and cell proliferation in acute myeloid leukemia cells. Blood Cancer J. 2014; 4:e228. PMC: 4219447. DOI: 10.1038/bcj.2014.49. View

12.

Ghaffari S, Shayan-Asl N, Jamialahmadi A, Alimoghaddam K, Ghavamzadeh A . Telomerase activity and telomere length in patients with acute promyelocytic leukemia: indicative of proliferative activity, disease progression, and overall survival. Ann Oncol. 2008; 19(11):1927-34. DOI: 10.1093/annonc/mdn394. View

13.

Ka H, Park H, Jung H, Choi J, Cho K, Ha J . Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells. Cancer Lett. 2003; 196(2):143-52. DOI: 10.1016/s0304-3835(03)00238-6. View

14.

Tallman M . What is the role of arsenic in newly diagnosed APL?. Best Pract Res Clin Haematol. 2008; 21(4):659-66. DOI: 10.1016/j.beha.2008.09.002. View

15.

Steelman L, Pohnert S, Shelton J, Franklin R, Bertrand F, McCubrey J . JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004; 18(2):189-218. DOI: 10.1038/sj.leu.2403241. View

16.

Wang R, Wei Y, An Z, Zou Z, Xiao G, Bhagat G . Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science. 2012; 338(6109):956-9. PMC: 3507442. DOI: 10.1126/science.1225967. View

17.

Doudican N, Bowling B, Orlow S . Enhancement of arsenic trioxide cytotoxicity by dietary isothiocyanates in human leukemic cells via a reactive oxygen species-dependent mechanism. Leuk Res. 2009; 34(2):229-34. PMC: 2815001. DOI: 10.1016/j.leukres.2009.05.017. View

18.

Iland H, Seymour J . Role of arsenic trioxide in acute promyelocytic leukemia. Curr Treat Options Oncol. 2013; 14(2):170-84. DOI: 10.1007/s11864-012-0223-3. View

19.

Chen Y, Zhou Q, Zhang L, Wang R, Jin M, Qiu Y . Idelalisib induces G1 arrest and apoptosis in chronic myeloid leukemia K562 cells. Oncol Rep. 2016; 36(6):3643-3650. DOI: 10.3892/or.2016.5176. View

20.

Markham A . Idelalisib: first global approval. Drugs. 2014; 74(14):1701-7. DOI: 10.1007/s40265-014-0285-6. View