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Improved therapy for clear cell renal cell carcinoma: beta-hydroxybutyrate and quercetin target hypoxia-induced angiogenesis and multidrug resistance

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Abstract

Background

Clear cell renal cell carcinoma (ccRCC) is a form of kidney cancer characterized by dysregulated angiogenesis and multidrug resistance. Hypoxia-induced tumor progression plays a crucial role in ccRCC pathogenesis. Beta-hydroxybutyrate (BHB) and quercetin (QCT) have shown potential in targeting angiogenesis and drug resistance in various cancer types. This study investigates the combined effects of BHB and QCT in hypoxia-induced Caki-1 cells.

Methods

Caki-1 cells were subjected to normoxic and hypoxic conditions and treated with BHB, QCT, or a combination of both. Cell-viability was assessed using the MTT assay, and mRNA expression levels of key angiogenesis-related genes (HIF-1α/2α, VEGF, Ang-1, Ang-2, and MDR4) were quantified through real-time PCR during 24 and 48 h.

Results

BHB and QCT treatments, either alone or in combination, significantly reduced cell-viability in Caki-1 cells (p < 0.05). Moreover, the combined therapy demonstrated a potential effect in downregulating the expression of angiogenesis-related genes and MDR4 in hypoxia-induced cells, with a marked reduction in HIF-1α/2α, VEGF, Ang-1, and MDR4 expression (p < 0.05). The expression of Ang-2 increases significantly in presence of BHB combined QCT treatment.

Conclusion

This study highlights the promising potential of a combination therapy involving BHB and QCT in mitigating angiogenesis and MDR4 expression in hypoxia-induced ccRCC cells. These findings support further investigation into the underlying mechanisms and warrant clinical studies to evaluate the therapeutic value of this combined treatment for ccRCC patients. This research provides new insights into addressing the challenges posed by angiogenesis and drug resistance in ccRCC.

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Information and resources availability

This article contains all data created and examined throughout this investigation. The corresponding author will provide datasets used or analyzed during the current work upon reasonable request.

Abbreviations

RCC:

Renal cell carcinoma

ccRCC:

Clear cell renal cell carcinoma

HIFα:

Hypoxia-inducible factor alpha

VHL:

Von Hippel-Lindau protein

VEGF:

Vascular endothelial growth factor

Ang-1:

Angiopoietin-1

MDR:

Multidrug resistance

EMT:

Epithelial–mesenchymal transition

BHB:

Beta-hydroxybutyrate

QCT:

Quercetin

KD:

Ketogenic diet

CMap:

Connectivity Map

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

DMSO:

Dimethyl sulfoxide

cDNA:

Complementary DNA

RT-qPCR:

Real-time reverse transcription-polymerase chain reaction

SD:

Standard deviation

ANOVA:

Analysis of variance

PTMs:

Posttranslational modifications

ACAT1:

Acetyl-CoA acyltransferase 1

GSC:

Glioma stem cells

ROS:

Reactive oxygen species

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Author notes

  1. Nima Mohammadipoor and Raika Naiebi have contributed equally to this work.

Authors and Affiliations

  1. Department of Nutrition, School of Public Health, Iran University of Medical Science, Tehran, Iran

    Nima Mohammadipoor

  2. Department of Hematology and Blood Banking, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Raika Naiebi

  3. Student Research Committee, Azerbaijan Medical University, Baku, Azerbaijan

    Seyed Amirhossein Mazhari

  4. Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Fateme Amooei & Marzieh Owrang

  5. Reproductive Biology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Fateme Amooei

  6. Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Marzieh Owrang

  7. School of Neurobiology Sciences, University of Utah, Salt Lake City, UT, 84112, USA

    Sahar Dastghaib

  8. Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran

    Mesbah Shams & Sanaz Dastghaib

  9. Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, P.O. Box: 71348-45794, Shiraz, Iran

    Mohammad Hassan Maleki

  10. Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Sanaz Dastghaib

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Contributions

All experiments, statistical analysis, and figure preparation were conducted by NM, RN, SAM, FA, MO. The initial draft of manuscript was written by NM, SD, and MS. All tests were set up by MHM and second draft of manuscript was written by MHM. A final manuscript proof was completed by SD and MHM who also contributed more funds to the project. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Mohammad Hassan Maleki or Sanaz Dastghaib.

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Mohammadipoor, N., Naiebi, R., Mazhari, S.A. et al. Improved therapy for clear cell renal cell carcinoma: beta-hydroxybutyrate and quercetin target hypoxia-induced angiogenesis and multidrug resistance. Mol Biol Rep 51, 379 (2024). https://doi.org/10.1007/s11033-024-09355-2

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  • DOI: https://doi.org/10.1007/s11033-024-09355-2

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