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Phloretin induces G2/M arrest and apoptosis by suppressing the β-catenin signaling pathway in colorectal carcinoma cells

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Abstract

Colorectal carcinoma (CRC) is the third most prevalent cancer, causing a significant mortality worldwide. Present available therapies are surgery, chemotherapy including radiotherapy, and these are known to be associated with heavy side effects. Therefore, nutritional intervention in the form of natural polyphenols has been well recognised to prevent CRC. Phloretin, a known dihydrochalcone is present in apple, pear and strawberry. This has been proven to induce apoptosis in cancer cells and also exhibited anti-inflammatory activity, thus can be explored as a potential anticancer nutraceutical agent. This study demonstrated phloretin’s significant in vitro anticancer activity against CRC. Phloretin suppressed cell proliferation, colony forming ability and cellular migration in human colorectal cancer HCT-116 and SW-480 cells. Results also revealed that phloretin generated reactive oxygen species (ROS) which provoked depolarization of mitochondrial membrane potential (MMP) and further contributed to cytotoxicity in colon cancer cells. Phloretin also modulated the cell cycle regulators including cyclins and cyclin-dependent kinases (CDKs) and halted cell cycle at G2/M phase. Moreover, it also induced apoptosis by regulating the expression of Bax and BCl-2. The Wnt/β-catenin signaling is inactivated by phloretin by targeting the downstream oncogenes namely CyclinD1, c-Myc and Survivin which are involved in the proliferation and apoptosis of colon cancer cells. In our study we showed that lithium chloride (LiCl) induced the expression of β-catenin and its target genes and the co-treatment of phloretin circumvent its effect and downregulated the Wnt/β-catenin signaling. In conclusion, our results strongly suggested that phloretin can be utilized as a nutraceutical anticancer agent for combating CRC.

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Data availability

All the data generated or analyzed during the study are included in this article or are available upon request.

Abbreviations

CDKs :

Cyclin dependent Kinases

CRC :

Colorectal cancer

DCFH:

-DA 2’-7’dichlorofluorescin diacetate

DMEM :

Dulbecco’s modified eagle medium

FBS :

Fetal Bovine serum

IC50 :

Inhibitory concentration

IEC-6:

Intestinal epithelial cells

JC-1:

Tetraethylbenzimidazolylcarbocyanine iodide

LiCl:

Lithium chloride

MMP:

Mitochondrial membrane potential

qRT-PCR:

Quantitative real time polymerase chain reaction

ROS:

Reactive oxygen species

SI:

Selectivity index

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Acknowledgements

The authors are highly thankful to the Director, CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, India for his support and providing all the necessary facilities. SK is highly grateful to the Indian Council of Medical Research, New Delhi for providing the ICMR-JRF fellowship and to the Academy of Scientific and Innovative Research (AcSIR), Ghaziabad for Ph.D. registration. CSIR-IHBT communication number for this manuscript is 5103.

Funding

This study was supported by grants from the CSIR project MLP 0155 and MLP0204.

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Authors and Affiliations

  1. Pharmacology and Toxicology Lab, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Himachal Pradesh, Palampur, 176 061, India

    Smita Kapoor & Yogendra S. Padwad

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Smita Kapoor & Yogendra S. Padwad

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SK: Conceptualization, Methodology, Validation, Formal analysis, writing original draft. YSP: Conceptualization, Resources, Review and editing, Investigation, Supervision, Funding acquisition. Both authors approved the final version of the manuscript.

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Correspondence to Yogendra S. Padwad.

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Kapoor, S., Padwad, Y.S. Phloretin induces G2/M arrest and apoptosis by suppressing the β-catenin signaling pathway in colorectal carcinoma cells. Apoptosis 28, 810–829 (2023). https://doi.org/10.1007/s10495-023-01826-4

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