Sensitization of philadelphia positive acute lymphoblastic leukemia cells resistant to imatinib by targeting sphingolipid metabolism
Kiraz, Yağmur, author.

Sensitization of philadelphia positive acute lymphoblastic leukemia cells resistant to imatinib by targeting sphingolipid metabolism

Kiraz, Yağmur, author.

Yazar Ek Girişi
Kiraz, Yağmur, author.

Fiziksel Tanımlama
xiv, 123 leaves: charts;+ 1 computer laser optical disc

Philadelphia positive acute lymphoblastic leukemia (Ph+ALL) is a common subtype of ALL and characterized by having BCR/ABL translocation. Tyrosine kinase inhibitors (TKI) such as imatinib are used for the treatment in Ph+ALL, however, 60- 75% of the patients can develop resistance against the TKIs. Bioactive sphingolipids are a group of lipids that play roles in various cellular mechanisms. Previous studies showed that sphingolipids and genes in the pathway were involved in response to TKI treatment in Ph+ALL. Here, we investigated the roles of SPL on the growth inhibitory effects of imatinib and exploit sphingolipid metabolism by majorly inhibiting glucosylceramide synthase (GCS) to accumulate ceramide or sphingosine to further sensitize cells to imatinib and/or overcome resistance to imatinib in Ph+ALL. Firstly, we detected that, sphingosine kinase-1 (SK-1) a well-studied SPL enzyme inhibition did not contribute to cytotoxic effects of imatinib in SD-1 Ph+ALL cells. Moreover, we determined that imatinib is inducing de novo synthesis pathway of SPL and increasing the levels of ceramide, sphingosine, hexosylceramides and sphingomyelin in SD-1 cells. Interestingly, newly generated imatinib-resistant cell line SD-1R was detected to have an aberration in this pathway resulting in development of resistance. Combination treatment with eliglustat (GCS inhibitor) resulted in a significant increase in ceramide and sphingosine levels and reflected on cell growth and sensitized cells to imatinib. Taken together, it was shown for the first time in the literature that the cytotoxic effects of imatinib was due to induction of de novo synthesis pathway of sphingolipids and inhibition of GCS together with imatinib has synergistic cytotoxic effects on imatinib resistant Ph+ALL cells. As a conclusion, increasing the intracellular levels of ceramide (and/or sphingosine) can be a novel approach to sensitize drug resistant Ph+ALL cells.

Konu Başlığı
Molecular biology.
Leukemia -- Genetic aspects.

Yazar Ek Girişi
Baran, Yusuf

Tüzel Kişi Ek Girişi
İzmir Institute of Technology. Molecular Biology and Genetics.

Tek Biçim Eser Adı
Thesis (Doctoral)--İzmir Institute of Technology: Molecular Biology and Genetics.
İzmir Institute of Technology: Molecular Biology and Genetics.--Thesis (Doctoral).

Elektronik Erişim
Access to Electronic Versiyon.

KütüphaneMateryal TürüDemirbaş NumarasıYer NumarasıDurumu/İade Tarihi
IYTETezT002139QH506 .K58 2019Tez Koleksiyonu