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In Vitro Characterization of Renal Drug Transporter Activity in Kidney Cancer

Pedro Caetano-Pinto1, Nathanil Justian1, Maria Dib1

  • 1Department of Urology, University Medicine Greifswald, 17475 Greifswald, Germany.

International Journal of Molecular Sciences
|September 9, 2022
PubMed

Insights

Kidney cancer cells retain drug transporter activity, impacting chemotherapy. Methylation inhibition boosts cisplatin toxicity in renal cell carcinoma (RCC) by enhancing organic cation uptake.

Area of Science:

  • Nephrology
  • Oncology
  • Molecular Biology

Background:

  • Drug transporters are crucial for kidney function and are well-characterized in normal renal proximal tubule epithelial cells (RPTECs).
  • The role of drug transporters in the pathophysiology of kidney cancer remains largely unknown.
  • Understanding these transporters is key to developing effective cancer therapies.

Purpose of the Study:

  • To investigate the activity, expression, and regulation of renal drug transporters in renal cell carcinoma (RCC) cell lines.
  • To assess the impact of methylation and epidermal growth factor receptor (EGFR) inhibition on drug transporter function and cisplatin cytotoxicity in RCC.
  • To compare transporter activity in RCC cells with non-malignant RPTECs.

Main Methods:

  • Utilized various RCC cell lines and a non-malignant RPTEC cell line for in vitro studies.
  • Analyzed drug uptake and efflux activity, transporter expression, and cisplatin cytotoxicity.
  • Investigated the effects of methylation inhibition and EGFR inhibition on transporter mechanisms.

Main Results:

  • RCC cells exhibited significant drug transporter activity, including nuclear localization of P-glycoprotein.
  • Pharmacological inhibition of P-glycoprotein increased cisplatin toxicity in normal RPTECs.
  • Methylation inhibition enhanced cisplatin toxicity in RCC cells by upregulating organic cation uptake.
  • Observed differential regulation of transporters by methylation and EGFR, indicating cellular heterogeneity.
  • Non-malignant RPTECs lacked organic cation transport machinery, highlighting functional changes in cancer cells.

Conclusions:

  • Renal cell carcinoma cells maintain substantial drug transporter activity, potentially influencing chemotherapeutic efficacy.
  • Drug transporter expression and regulation are heterogeneous in RCC and can be modulated by factors like methylation.
  • Targeting specific drug transporters or regulatory pathways may offer novel therapeutic strategies for kidney cancer.
Keywords:
drug transporternephrotoxicityproximal tubule epithelial cellsrenal cell carcinoma

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