Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells


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Sahin H. N. , Adan A.

TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI, 2022 (Journal Indexed in SCI) identifier

  • Publication Type: Article / Article
  • Publication Date: 2022
  • Doi Number: 10.1515/tjb-2021-0152
  • Title of Journal : TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI
  • Keywords: apoptosis, FLT3 wild type AML, midostaurin, sphingosine kinase, sphingosine kinase inhibitor, apoptoz, FLT3 yabanil tip AML, midostaurin, sfingozin kinaz, sfingozin kinaz inhibitoru, APOPTOSIS, SPHINGOLIPIDS, CHEMOTHERAPY, COMBINATION, RESISTANCE, THERAPY, PKC412, GROWTH, TRIAL

Abstract

Objectives Therapeutic potential of clinically approved FLT3 inhibitor midostaurin has been neglected in wild-type FLT3 positive acute myeloid leukemia (AML). Sphingosine kinase-1 (SK-1) having anti-proliferative functions is studied in various cancers, but not in FLT3 wild-type AML. We aimed to develop new therapeutic strategies to combat FLT3 wild-type AML by combining midostaurin with SK-1 inhibitor (SKI II) in THP1 cells. Methods The anti-proliferative effects of midostaurin, SKI II and in combination on THP1 cells were determined by MTT assay. The combination indexes were calculated using calcusyn software. SK-1 expression and PARP cleavage were checked by western blot. Cell cycle distributions (PI staining) and apoptosis (annexin-V/PI dual staining) were assessed by flow cytometry for each agent alone and in combinations. Results Midostaurin decreased SK-1 protein level. Midostaurin, SKI II and certain combinations decreased cell viability in a dose dependent manner. The combined anti-leukemic effects of the aforementioned drug combination afforded additive effect. Co-administration induced both necrosis and apoptosis via phosphatidylserine externalization, PARP cleavage and cell cycle arrest at G0/G1 and S phases. Conclusions Targeting sphingosine kinase-1 together with FLT3 inhibition could be a novel mechanism to increase limited clinic response to midostaurin in wild-type FLT3 overexpressing AML after further pre-clinical studies.