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Synergistic anti-proliferative and apoptotic effect of NVP-BEZ235 and curcumin on human SH-SY5Y neuroblastoma cells

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Abstract

Neuroblastoma, a tumor of the sympathetic nervous system, is one of the most common tumors found in children. Most patients develop resistance to therapy and show poor prognosis, thus there is a need of novel therapeutic agents for the treatment of neuroblastoma. NVP-BEZ235 is a dual Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor that induces apoptosis and suppresses the growth of cancer. Curcumin acts as an anticancer agent in certain cancers. This study investigated the synergetic effect of NVP-BEZ235 and curcumin against neuroblastoma SH-SY5Y cell line. In the current study, the synergic effect of NVP-BEZ235 and curcumin in SH-SY5Y was examined in terms of the cell growth by cell viability and colony forming assay, cell cycle and apoptotic cell death by flow cytometry and mRNA expression levels by quantitative Real Time Polymerase Chain Reaction (qRT-PCR). Curcumin, NVP-BEZ235 or a combination of both, showed cytotoxicity in a dose and time dependent manner in SH-SY5Y cells. 10 µM curcumin and 200 nM NVP-BEZ235 were chosen as combination therapy, as the combination index showed synergism. Colony forming assay showed decrease in cell growth in combination group. The cell cycle distribution for combination group demonstrated a decrease in G0/G1 phase at 48 h. Annexin V showed an anticancer effect in combination group when compared to control group. Moreover, qRT-PCR results showed a significant increase in caspase 3, caspase 7, Bax and p53 genes, while a decrease in Bcl-2 gene expression levels. These findings suggest that combination therapy of NVP-BEZ235 and curcumin may be a promising therapeutic candidate for treatment of neuroblastoma.

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Data availability

The datasets used and/or analyzed in the present study are available from the corresponding author upon reasonable request.

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Acknowledgements

SH-SY5Y and HUVEC cell lines were a kind gift from Prof. F. Sahin at Yeditepe University. In vitro cell culture experiments were conducted in Department of Molecular Biology and Genetics, at Istanbul Sabahattin Zaim University.

Funding

This work was supported by the Scientific Research Project (BAP) of Istanbul Sabahattin Zaim University with the grant number BAP:1000-102.

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Authors and Affiliations

  1. Sabri Ulker R&D Center, Istanbul Sabahattin Zaim University, Kucukcekmece, Istanbul, Turkey

    Fadime Çetin, Sifa Kosba & Hüseyin Abdik

  2. Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Sabahattin Zaim University, Kucukcekmece, Istanbul, 34303, Turkey

    Hüseyin Abdik & Zeynep Busra Bolat

  3. Molecular Biology and Genetics Department, Hamidiye Institute of Health Sciences, University of Health Sciences- Turkey, Istanbul, 34668, Turkey

    Zeynep Busra Bolat

  4. Experimental Medicine Research and Application Center, Validebag Research Park, University of Health Sciences, Uskudar, Istanbul, 34662, Turkey

    Zeynep Busra Bolat

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  1. Fadime Çetin
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Contributions

FC Conceptualization, methodology, investigation of in vitro cell culture studies and writing- original draft. SK Methodology, investigation of cell viability and cell cycle studies, and writing- original draft. HA Resources, supervised data analysis, reviewing and revising the manuscript. ZBB Design the study, guided the conduct of studies, funding acquisition, writing and revising the manuscript.

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Correspondence to Zeynep Busra Bolat.

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Çetin, F., Kosba, S., Abdik, H. et al. Synergistic anti-proliferative and apoptotic effect of NVP-BEZ235 and curcumin on human SH-SY5Y neuroblastoma cells. Med Oncol 41, 11 (2024). https://doi.org/10.1007/s12032-023-02239-8

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