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Nanoemulsion potentiates the anti-cancer activity of Myricetin by effective inhibition of PI3K/AKT/mTOR pathway in triple-negative breast cancer cells

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Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous tumor with a poor prognosis and high metastatic potential, resulting in poor clinical outcomes, necessitating investigation to devise effective therapeutic strategies. Multiple studies have substantiated the anti-cancer properties of the naturally occurring flavonoid "Myricetin" in various malignancies. However, the therapeutic application of Myricetin is impeded by its poor water solubility and low oral bioavailability. To overcome this limitation, we aimed to develop nanoemulsion of Myricetin (Myr-NE) and evaluate its advantage over Myricetin alone in TNBC cells. The nanoemulsion was formulated using Capryol 90 (oil), Tween 20 (surfactant), and Transcutol HP (co-surfactant). The optimized nano-formulation underwent an evaluation to determine its size, zeta potential, morphology, stability, drug encapsulation efficiency, and in vitro release properties. The anti-cancer activity of Myr-NE was further studied to examine its distinct impact on intracellular drug uptake, cell-viability, anti-tumor signaling, oxidative stress, clonogenicity, and cell death, compared with Myricetin alone in MDA-MB-231 (TNBC) cells. The in vitro drug release and intracellular drug uptake of Myricetin was significantly increased in Myr-NE formulation as compared to Myricetin alone. Moreover, Myr-NE exhibited significant inhibition of cell proliferation, clonogenicity, and increased apoptosis with ~ 2.5-fold lower IC50 as compared to Myricetin. Mechanistic investigation revealed that nanoemulsion augmented the anti-cancer efficacy of Myricetin, most likely by inhibiting the PI3K/AKT/mTOR pathway, eventually leading to enhanced cell death in TNBC cells. The study provides substantial experimental evidence to support the notion that the Myr-NE formulation has the potential to be an effective therapeutic drug for TNBC treatment.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

PS acknowledges the Indian Council of Medical Research for fellowship support [Grant number 45/24/20202-Nan-BMS]. We also acknowledge Ms. Namita Kalra for helping with the data acquisition on the flow cytometer.

Funding

This work was supported by the Indian Council of Medical Research [Grant number 45/24/20202-Nan-BMS]. Author PS has received fellowship support from the Indian Council of Medical Research.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Hamdard University), New Delhi, 110062, India

    Preeti Sharma, Mohammad Ahmed Khan, Abul Kalam Najmi & Mohd. Akhtar

  2. Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO, Timarpur, Delhi, 110054, India

    Preeti Sharma, Shubhra Chaturvedi, Yogesh Rai, Anant Narayan Bhatt & Anil Kumar Mishra

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PS: Conceptualization, investigation, methodology, data curation, Writing—original draft. SC: Formal analysis, writing—review & editing. MK: Formal analysis, writing—review & editing. YR: In vitro investigation, review & editing. AB: In vitro data analysis, review & editing. MA: Writing—review & editing. AM: Formal analysis—review & editing.

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Sharma, P., Chaturvedi, S., Khan, M.A. et al. Nanoemulsion potentiates the anti-cancer activity of Myricetin by effective inhibition of PI3K/AKT/mTOR pathway in triple-negative breast cancer cells. Med Oncol 41, 56 (2024). https://doi.org/10.1007/s12032-023-02274-5

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