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Differential in vitro anti-leukemic activity of resveratrol combined with serine palmitoyltransferase inhibitor myriocin in FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) carrying AML cells

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Abstract

Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) AML is restricted due to toxicity, drug resistance and relapse eventhough targeted therapies are clinically available. Resveratrol with its multi-targeted nature is a promising chemopreventive remaining limitedly studied in FLT3-ITD AML regarding to ceramide metabolism. Here, its cytotoxic, cytostatic and apoptotic effects are investigated in combination with serine palmitoyltransferase (SPT), the first enzyme of de novo pathway of ceramide production, inhibitor myriocin on MOLM-13 and MV4-11 cells. We assessed dose-dependent cell viability, flow cytometric cell death and cell cycle profiles of resveratrol in combination with myriocin by MTT assay, annexin-V/PI staining and PI staining respectively. Resveratrol’s dose-dependent effect on SPT protein expression was also checked by western blot. Resveratrol decreased cell viability in a dose- dependent manner whereas myriocin did not affect cell proliferation effectively in both cell lines after 48h treatments. Although resveratrol induced both apoptosis and a significant S phase arrest in MV4-11 cells, it triggered apoptosis and non-significant S phase accumulation in MOLM-13 cells. Co-administrations reduced cell viability. Increased cytotoxic effect of co-treatments was further proved mechanistically through induction of apoptosis via phosphatidylserine relocalization. The cell cycle alteration in co-treatment was significant with an S phase arrest in MV4-11 cells, however, it was not effective on cell cycle progression of MOLM-13 cells. Resveratrol also increased SPT expression. Overall, modulation of SPT together with resveratrol might be the possible explanation for resveratrol’s action. It could be an integrative medicine for FLT3-ITD AML after investigating its detailed mechanism of action in relation to de novo pathway of ceramide production.

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Acknowledgements

The authors acknowledge Genome and Stem Cell Center of Erciyes University for providing the flow cytometry facility. We are grateful to Esma Saraymen, the specialist, for flow cytometry measurements.

Funding

This study was supported by Abdullah Gul University Scientific Research Projects Coordination Unit with Project No: FAB-2016-66.

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Authors and Affiliations

  1. Bioengineering Program, Graduate School of Engineering and Science, Abdullah Gul University, Kayseri, Turkey

    Nur Şebnem Ersöz

  2. Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, Turkey

    Aysun Adan

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  1. Nur Şebnem Ersöz
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Conceptualization: AA; Acquisition, analysis or interpretation of data: NŞE, AA; Writing - review and editing: NŞE, AA; Approval of the final version: NŞE, AA; Supervision and principal author: AA.

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Correspondence to Aysun Adan.

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Ersöz, N.Ş., Adan, A. Differential in vitro anti-leukemic activity of resveratrol combined with serine palmitoyltransferase inhibitor myriocin in FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) carrying AML cells. Cytotechnology 74, 271–281 (2022). https://doi.org/10.1007/s10616-022-00527-1

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