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Repositioning of simvastatin for diabetic colon cancer: role of CDK4 inhibition and apoptosis

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Abstract

There is increased risk of colon cancer in both men and women having diabetes. The objective of the study was to evaluate the role of simvastatin in colon cancer associated with type 2 diabetes mellitus. Diabetes was induced by administering high fat diet with low dose streptozotocin model. 1,2 dimethylhydrazine (25 mg/kg, sc) was used for colon cancer induction. MTT assay, scratch assay, clonogenic assay and annexin V-FITC assay using flow cytometry were performed on HCT-15 cell line. Simvastatin controlled diabetes and colon cancer in animal models and reduced mRNA expression of CDK4 in colon tissues. In vitro studies revealed that simvastatin showed a decrease in cell viability and produced dose dependent decrease in clone formation. There was decrease in the rate of migration with increase in concentration of simvastatin in scratch assay. Moreover, simvastatin induced apoptosis as depicted from annexin V-FITC assay using flow cytometry as well as that revealed by tunnel assay. Our data suggest that simvastatin exhibits protective role in colon cancer associated with diabetes mellitus and acts possibly via down regulation of CDK4 and induction of apoptosis and hence can be considered for repositioning in diabetic colon cancer.

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Data availability

The data used in the current study are available from the corresponding author on reasonable request.

Abbreviations

5-FU:

5-Fluorouracil

CDKs:

Cyclin dependent kinases

CEA:

Carcino embryogenic antigen

CMC:

Carboxy methyl cellulose

DEPC:

Diethyl pyrocarbonate

DMH:

1, 2-Dimethylhydrazine

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GLUT-1:

Glucose transporter-1

GSH:

Reduced glutathione

HbA1c:

Glycosylated hemoglobin

HUVEC:

Human umbilical vein endothelial cells

MDA:

Malondialdehyde

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OGTT:

Oral glucose tolerance tests

PBS:

Phosphate buffer saline

PI:

Propidium iodide

PS:

Phosphatidylserine

RNA:

Ribonucleic acid

RPMI:

Roswell Park Memorial Institute medium

SOD:

Super-oxide dismutase

TUNEL:

Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors express their sincere gratitude towards the Institute of Pharmacy, Nirma University, Ahmedabad, India for providing all the essential amenities in making this research paper.

Funding

No funding was received for conducting this study.

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Authors and Affiliations

  1. Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, 382 481, India

    Saumitra Gajjar & Vivek Bora

  2. National Forensic Sciences University, Gandhinagar, India

    Bhoomika M. Patel

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  1. Saumitra Gajjar
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  2. Vivek Bora
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Contributions

SG and VB carried out the study, collected and interpreted the data and wrote the manuscript. BMP designed the study, arranged the funds, guided for study protocol, data interpretation and manuscript writing and approved the manuscript. All the data were generated in-house and that no paper mill was used.

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Correspondence to Bhoomika M. Patel.

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No potential commercial or financial relationships are involved in the present work and the authors declare that no conflicts of interest are involved in the present research work.

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The experimental work was performed after approval from the Institutional Animal Ethics Committee (IAEC), Institute of Pharmacy, Nirma University, Ahmedabad (Protocol approval no. IP/PCOL/PHD/26/2019/007), as per the regulations of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.

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Gajjar, S., Bora, V. & Patel, B.M. Repositioning of simvastatin for diabetic colon cancer: role of CDK4 inhibition and apoptosis. Mol Cell Biochem 478, 2337–2349 (2023). https://doi.org/10.1007/s11010-023-04663-w

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