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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
15:43

Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

Published on: January 7, 2013

Inhibition of apoptotic proteins causes multidrug resistance in renal carcinoma cells

J M Scheltema1, J C Romijn, G J van Steenbrugge

  • 1Department of Urology, Erasmus University and Academic Hospital, Rotterdam, The Netherlands.

Anticancer Research
|February 19, 2002
PubMed

Insights

Multidrug resistance in renal cell carcinoma (RCC) involves apoptosis inhibition, not just P-glycoprotein or topoisomerase II activity. Novel agents CC-313 and DiMIQ induce necrosis, bypassing this resistance effectively.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Renal Cell Carcinoma (RCC) often shows resistance to chemotherapy, potentially due to multidrug resistance (MDR) genes.
  • Mechanisms like P-glycoprotein (Pgp) overexpression and attenuated DNA-topoisomerase II (topoII) activity (at-MDR) are known contributors to RCC drug resistance.
  • The role of apoptosis regulation in MDR and the systematic cytotoxicity of various agents in RCC remain underexplored.

Purpose of the Study:

  • To investigate apoptosis prevention as a mechanism of MDR in RCC.
  • To assess the cytotoxicity of diverse chemotherapeutic agents in RCC cell lines.
  • To correlate Bcl-2 and Bax expression with apoptotic activity and cell death in MDR RCC.

Main Methods:

  • Immunohistochemistry and Western blotting were used to determine Bcl-2 and Bax expression in MDR RCC lines.
  • Cell lines were treated with cytotoxic agents, and cell death was analyzed using Hoechst 33342 and propidium iodide staining.
  • MTT assays quantified cell viability to assess drug cytotoxicity and resistance.

Main Results:

  • MDR RCC sublines showed decreased Bax and increased Bcl-2 expression, indicating apoptosis inhibition as a feature of MDR.
  • Significant resistance was observed for most drugs, with exceptions being CC-313 and DiMIQ.
  • CC-313 and DiMIQ induced necrotic cell death, unlike other agents that induced apoptosis.

Conclusions:

  • Multidrug resistance in chemoselected RCC sublines is mediated by apoptosis inhibition, independent of MDR1 and at-MDR.
  • CC-313 and DiMIQ demonstrate potent cytotoxicity in RCC, likely due to their induction of necrotic cell death.
  • Targeting apoptosis pathways presents a potential strategy for overcoming MDR in renal cell carcinoma treatment.

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