Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets.
Melanoma is the most aggressive form of skin cancer. Patients with advanced disease, such as lymph node involvement and distant metastases, have 5-year survival rates of 50% and 10-20%, respectively. This poor prognosis largely results from resistance to conventional chemotherapy, namely cytotoxic drugs. The basis for drug resistance in melanoma is most likely dysregulation of apoptosis, although other mechanisms including drug transport, detoxification, and enhanced DNA repair may also play a role. Defects at multiple levels and in both major apoptotic pathways have been described in melanoma. Our laboratory has identified an inhibitor of apoptosis, termed survivin, that is expressed in melanoma and required for maintenance of melanoma cell viability. Targeting of survivin and other apoptotic regulators increases the sensitivity of melanoma cells to cytotoxic drugs, and may provide a promising new therapeutic approach to cancer.
Grossman
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Department of Dermatology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.
Altieri
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D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53