Dihydrodiol dehydrogenase in drug resistance and sensitivity of human carcinomas.
We previously reported (UroOncology 1:165, 2001) cross-resistance and collateral-sensitivity to 2-chlorodeoxyadenosine (CldAdo) and fludarabine (FaraA), respectively, in a human renal cell carcinoma selected for resistance to 2'-deoxytubercidin (Caki-dTub). Insofar that these drugs generally demonstrate cross resistance rather than collateral sensitivity, we further examined the bases for this phenomenon. Both CldAdo and FaraA induce apoptosis, as the triphosphates, via binding to Apaf-1. In the presence of cytochrome c, this binding leads to activation of procaspase 9 to active caspase 9 that induces apoptosis through its activation of caspase 3. CldAdo and FaraA induced caspase 3 activities in wild type and Caki-dTub cell lines in a dose-dependent manner that paralleled the cross-resistance (CldAdo, 200-fold) or collateral sensitivity (FaraA, 20-fold) with regard to cell viability. The activation of caspase 3 was inhibited by the caspase 9 inhibitor, Z-LEHD-FMK, suggesting that both drugs act via the same pathway. By differential display and direct enzyme analysis, dihydrodiol dehydrogenase (DDH) was observed to be profoundly underexpressed in the Caki-dTub compared to wild-type Caki-1 cells. Stable transfection of the Caki-dTub cells with a vector encoding the enzyme led to partial reversal of the resistance to CldAdo. Resistance to cisplatin has recently been ascribed to overexpression of DDH in a human ovarian carcinoma cell line (Deng et al. in J Biol Chem 227:15035, 2002). It is tempting to speculate a mutation in the Apaf-1 nucleotide binding site that reduces (CldAdo) or increases (FaraA) toxicity in the Caki-dTub cells; however, the recent finding by others in a human ovarian carcinoma cell line suggests that DDH expression mediates the cross-resistance and perhaps, collateral-sensitivity.
Pan
Bih Fang
BF
Department 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
Nelson
J Arly
JA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D017338:Cladribine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D017338:Cladribine; D010088:Oxidoreductases; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; D053148:Caspase 3; D014740:Vidarabine; C024352:fludarabine