Molecular Pathways: GLI1-Induced Drug Glucuronidation in Resistant Cancer Cells
Autor: | Katherine L. B. Borden, Hiba Ahmad Zahreddine |
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Rok vydání: | 2015 |
Předmět: |
Cancer Research
Glycosylation Glucuronosyltransferase Antineoplastic Agents Drug resistance Pharmacology medicine.disease_cause Zinc Finger Protein GLI1 digestive system Article Glucuronic Acid Neoplasms medicine Animals Humans Vorinostat biology Cancer medicine.disease Multiple drug resistance Leukemia Oncology Drug Resistance Neoplasm Inactivation Metabolic Cancer cell biology.protein Carcinogenesis Transcription Factors medicine.drug |
Zdroj: | Clinical Cancer Research. 21:2207-2210 |
ISSN: | 1557-3265 1078-0432 |
Popis: | Drug resistance remains a major impediment in the development of durable cancer therapies. Studies in acute myelogenous leukemia (AML) patients revealed a new form of multidrug resistance. Here, increased glioma-associated protein GLI1 leads to elevation of the UDP-glucuronosyl transferase (UGT) enzymes. UGTs add glucuronic acid to xenobiotics and metabolites. Traditionally, the loss of these enzymes is thought to contribute to cancer as a result of impaired clearance of environmental carcinogens. However, we demonstrate that overexpression of UGTs can contribute to oncogenesis by promoting drug resistance. Indeed, UGT levels in AML patients treated with ribavirin and/or cytarabine were elevated at relapse relative to diagnosis. This was reversed by GLI1 inhibition, suggesting a clinically relevant strategy to overcome drug resistance. Further, overexpression of UGTs can also lead to drug resistance in other cancers, such as certain Hsp90 inhibitors and vorinostat in colorectal and chronic lymphoblastic leukemia, respectively. Not all drugs are targets of glucuronidation, suggesting that UGT status could be relevant to treatment choice. Here, we describe several facets of UGT biology and how these could be exploited clinically. These studies demonstrate how drugs in cancer cells can be metabolized differentially than their normal counterparts. In summary, we describe a new form of drug resistance relevant to a variety of cancer contexts. Clin Cancer Res; 21(10); 2207–10. ©2015 AACR. |
Databáze: | OpenAIRE |
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