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The potential impact of trigonelline loaded micelles on Nrf2 suppression to overcome oxaliplatin resistance in colon cancer cells

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Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) has a pivotal role in promoting chemoresistance by regulation of antioxidants and detoxification enzymes. Trigonelline is one of the major alkaloids in raw coffee which has been recently introduced as potent inhibitor of Nrf2. This study investigated the role of trigonelline and trigonelline loaded micelles in Nrf2 inhibition to break down oxaliplatin resistance in colon cancer cells. The PCL-PEG-PCL and PLA-PCL-PEG-PCL-PLA copolymers and trigonelline loaded micelles were prepared and characterized for fourier transforms infrared (FTIR), hydrogen nuclear magnetic resonance (1H-NMR), carbon nuclear magnetic resonance (13C-NMR) spectroscopy, particle size, zeta potential, scanning electron microscopy (SEM) and entrapment efficiency. Cell viability and apoptosis were evaluated by using MTT and flow cytometry assays, respectively. Nrf2, MRP1, NQO1, HO-1, Bax, and Bcl2 gene expressions were examined by qRT-PCR. Our results revealed that micelles had spherical shapes with narrow sizes and zeta potential indexes of − 9.06 ± 6.94 mV for trigonelline loaded 3Block and − 7.47 ± 6.08 mV for trigonelline loaded 5Block micelles. After Nrf2 inhibition by trigonelline, antioxidant response element (ARE) related gene expressions were decreased (p < 0.05) with a significantly higher impact by trigonelline loaded micelles (p < 0.05). Trigonelline loaded micelles also strongly decreased IC50 value of oxaliplatin in resistant colon cancer cells (p < 0.05). Furthermore, trigonelline loaded 5Block micelle increased oxaliplatin-induced apoptosis in a Nrf2/ARE dependent manner. Altogether, the current study suggests that delivery of trigonelline loaded micelles as potent Nrf2 inhibitors can be considered as a promising strategy to overcome oxaliplatin resistance in colon cancer patients.

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Acknowledgements

We thank Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran for financial support [95/126].

Funding

This work financially was supported by Drug Applied Research Center, Tabriz University of Medical Sciences, and Tabriz, Iran [95/126].

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Authors and Affiliations

  1. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Abbas Pirpour Tazehkand & Nasser Samadi

  2. Department of Clinical Biochemistry and Laboratories Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Abbas Pirpour Tazehkand & Nasser Samadi

  3. Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran

    Roya Salehi

  4. Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Kobra Velaei

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  1. Abbas Pirpour Tazehkand
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Electronic supplementary material

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11033_2020_5650_MOESM1_ESM.pdf

Supplementary material 1 (PDF 168 kb) Online Resource 1. Ring opening polymerization of PCL-PEG-PCL and PLA-PCL-PEG-PCL-PLA co polymers and micelles preparation.

11033_2020_5650_MOESM2_ESM.pdf

Supplementary material 2 (PDF 247 kb) Online Resource 2. 1HNMR spectrum of PCL-PEG-PCL (3Block) and PLA-PCL-PEG-PCL-PLA (5Block) copolymers.

11033_2020_5650_MOESM3_ESM.pdf

Supplementary material 3 (PDF 197 kb) Online Resource 3. 13CNMR spectrum of PCL-PEG-PCL (3Block) and PLA-PCL-PEG-PCL-PLA (5Block) copolymers.

11033_2020_5650_MOESM4_ESM.pdf

Supplementary material 4 (PDF 220 kb) Online Resource 4. FTIR Spectra of PCL-PEG-PCL (3Block) and PLA-PCL-PEG-PCL-PLA (5Block) copolymers (A), trigonelline (Trig) loaded 3Block and trigonelline loaded 5Block micelles (B).

11033_2020_5650_MOESM5_ESM.pdf

Supplementary material 5 (PDF 156 kb) Online Resource 5. The combination index of oxaliplatin, trigonelline, trigonelline loaded 3Block and trigonelline loaded 5Block micelles in SW480 resistant colon cancer cells.

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Pirpour Tazehkand, A., Salehi, R., Velaei, K. et al. The potential impact of trigonelline loaded micelles on Nrf2 suppression to overcome oxaliplatin resistance in colon cancer cells. Mol Biol Rep 47, 5817–5829 (2020). https://doi.org/10.1007/s11033-020-05650-w

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