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Article

Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma

  • Authors:
    • Tariq Alqahtani
    • Vishnu Muthuraj Kumarasamy
    • Adam Huczyński
    • Daekyu Sun
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA, Faculty of Chemistry, Adam Mickiewicz University, 60‑780 Poznan, Poland
  • Pages: 348-358
    |
    Published online on: November 20, 2019
       https://doi.org/10.3892/ijo.2019.4916
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Abstract

Rearranged during transfection kinase (RET) is a validated molecular target in medullary thyroid cancer (MTC), as activating mutations in RET are often associated with the development of MTC. The present study reports the first preclinical characterization of salinomycin and selected analogs as potent RET transcriptional inhibitors. Reverse transcription‑PCR and immunoblotting revealed that salinomycin profoundly decreased RET expression in the TT human MTC cell line by inhibiting RET transcription. Moreover, salinomycin resulted in remarkable anti‑proliferative activity against MTC that is driven by RET (gain of function mutation) by selectively inhibiting the intracellular PI3K/Akt/mTOR signaling pathway. Also, flow cytometry and fluorescence‑activated cell sorting showed that salinomycin induces G1 phase arrest and apoptosis by reducing the expression of retinoblastoma protein, E2F1, cyclin D and CDK4. The structure‑activity relationship of salinomycin was investigated in this study. Some of the salinomycin derivatives showed the ability to reduce RET expression where others fail to alter RET expression. These results suggest that the RET‑suppressing effect of salinomycin may be largely attributed to disruption of the Wnt pathway, presumably through interference with the ternary LRP6‑Frizzled‑Wnt complex. Furthermore, these findings support the further preclinical evaluation of salinomycin and its analogs as a promising new class of therapeutic agents for the improved treatment of MTC.
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Copy and paste a formatted citation
Spandidos Publications style
Alqahtani T, Kumarasamy VM, Huczyński A and Sun D: Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma. Int J Oncol 56: 348-358, 2020.
APA
Alqahtani, T., Kumarasamy, V.M., Huczyński, A., & Sun, D. (2020). Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma. International Journal of Oncology, 56, 348-358. https://doi.org/10.3892/ijo.2019.4916
MLA
Alqahtani, T., Kumarasamy, V. M., Huczyński, A., Sun, D."Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma". International Journal of Oncology 56.1 (2020): 348-358.
Chicago
Alqahtani, T., Kumarasamy, V. M., Huczyński, A., Sun, D."Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma". International Journal of Oncology 56, no. 1 (2020): 348-358. https://doi.org/10.3892/ijo.2019.4916
Copy and paste a formatted citation
x
Spandidos Publications style
Alqahtani T, Kumarasamy VM, Huczyński A and Sun D: Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma. Int J Oncol 56: 348-358, 2020.
APA
Alqahtani, T., Kumarasamy, V.M., Huczyński, A., & Sun, D. (2020). Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma. International Journal of Oncology, 56, 348-358. https://doi.org/10.3892/ijo.2019.4916
MLA
Alqahtani, T., Kumarasamy, V. M., Huczyński, A., Sun, D."Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma". International Journal of Oncology 56.1 (2020): 348-358.
Chicago
Alqahtani, T., Kumarasamy, V. M., Huczyński, A., Sun, D."Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma". International Journal of Oncology 56, no. 1 (2020): 348-358. https://doi.org/10.3892/ijo.2019.4916
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