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Dihydrodiol dehydrogenase in drug resistance and sensitivity of human carcinomas

Bih Fang Pan1, J Arly Nelson

  • 1Department of Molecular Pathology, Unit 951, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, PO Box 301429, Houston, TX 77230-1429, USA. bpan@mdanderson.org

Cancer Chemotherapy and Pharmacology
|September 30, 2006
PubMed

Insights

This study investigated drug resistance in renal cell carcinoma, finding that dihydrodiol dehydrogenase (DDH) underexpression explains cross-resistance to 2-chlorodeoxyadenosine and collateral sensitivity to fludarabine.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Human renal cell carcinoma (Caki-dTub) exhibits cross-resistance to 2-chlorodeoxyadenosine (CldAdo) and collateral sensitivity to fludarabine (FaraA), contrary to typical drug resistance patterns.
  • Both CldAdo and FaraA, in their triphosphate forms, induce apoptosis by binding to Apaf-1, leading to caspase 9 and caspase 3 activation.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the observed cross-resistance and collateral sensitivity to CldAdo and FaraA in Caki-dTub cells.
  • To investigate the role of dihydrodiol dehydrogenase (DDH) in mediating these drug responses.

Main Methods:

  • Comparative analysis of caspase 3 activity in wild-type and Caki-dTub cell lines treated with CldAdo and FaraA.
  • Assessment of drug pathway involvement using a caspase 9 inhibitor (Z-LEHD-FMK).
  • Differential display and enzyme analysis to identify differences in enzyme expression between cell lines; stable transfection to restore enzyme function.

Main Results:

  • Caspase 3 activation by CldAdo and FaraA paralleled cell viability changes, with CldAdo showing 200-fold resistance and FaraA showing 20-fold collateral sensitivity.
  • Caspase 9 inhibition blocked drug-induced caspase 3 activation, confirming a shared apoptotic pathway.
  • Dihydrodiol dehydrogenase (DDH) was significantly underexpressed in Caki-dTub cells compared to Caki-1 cells. Restoration of DDH via transfection partially reversed CldAdo resistance.

Conclusions:

  • Underexpression of dihydrodiol dehydrogenase (DDH) is a key factor in the cross-resistance to CldAdo and collateral sensitivity to FaraA in this renal cell carcinoma model.
  • The findings suggest DDH expression levels can modulate responses to nucleoside analogs, offering potential therapeutic insights.
  • While Apaf-1 mutations were considered, DDH's role aligns with recent findings in other cancer types, highlighting its broader significance in drug resistance.

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