Cellulose nanocrystals derived from chicory plant: an un-competitive inhibitor of aromatase in breast cancer cells via PI3K/AKT/mTOP signalling pathway

Abstract

A significant contributing factor in the development of breast cancer is the estrogens. The synthesis of estrogens is primarily facilitated by aromatase (CYP19), a cytochrome P450 enzyme. Notably, aromatase is expressed at a higher level in human breast cancer tissue compared with the normal breast tissue. Therefore, inhibiting aromatase activity is a potential strategy in hormone receptor-positive breast cancer treatment. In this study, Cellulose Nanocrystals (CNCs) were obtained from Chicory plant waste through a sulfuric acid hydrolysis method with the objective of investigating that whether the obtained CNCs could act as an inhibitor of aromatase enzyme, and prevent the conversion of androgens to estrogens. Structural analysis of CNCs was carried out using Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD), while morphological results were obtained using AFM, TEM, and FE-SEM. Furthermore, the nano-particles were found to be spherical in shape with a diameter range of 35-37 nm and displayed a reasonable negative surface charge. Stable transfection of MCF-7 cells with CYP19 has demonstrated the ability of CNCs to inhibit aromatase activities and prevent cell growth by interfering with the enzyme activities. Spectroscopic results revealed the binding constant of CYP19-CNCs and (CYP19-Androstenedione)-CNCs complexes to be 2.07 × 10³ L/gr and 2.06 × 10⁴ L/gr, respectively. Conductometry and CD data reported different interaction behaviors among CYP19 and CYP19-Androstenedione complexes at the presence of CNCs in the system. Moreover, the addition of CNCs to the solution in a successive manner resulted in the enhancement of the secondary structure of the CYP19-androstenedione complex. Additionally, CNCs showed a marked reduction in the viability of cancer cells compared to normal cells by enhancing the expression of Bax and p53 at protein and mRNA levels, and by decreasing mRNA levels of PI3K, AKT, and mTOP, as well as protein levels of PI3Kg-P110 and P-mTOP, in MCF-7 cells after incubation with CNCs at IC₅₀ concentration. These findings confirm the decrease in proliferation of breast cancer cells associated with induction of apoptosis through down-regulation of the PI3K/AKT/mTOP signaling pathway. According to the provided data, the obtained CNCs are capable of inhibiting aromatase enzyme activity, which has significant implications for the treatment of cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cellulose nanocrystals
• chicory plant waste
• aromatase cytochrome P450
• spectroscopy
• un-competitive inhibitor
• breast cancer
• XRD
• FE-SEM

Disclosure statement

No potential conflict of interest was reported by the authors.

Acknowledgments

The technical and financial support of the Research Council of the Neyshabur Branch and Mashhad Branch, Islamic Azad Universities, are gratefully acknowledged.

Author contributions

All the authors contributed to the processes of data analysis, drafting, and critically revising the paper and agreed to be accountable for all the aspects of the work.

Availability of data and materials

Data available on request from the authors. The data that support the findings of this study are available from the corresponding author, [author initials], upon reasonable request.

Additional information

Funding

Islamic Azad University of Mashhad Branch, Mashhad, Iran.