In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity. implications in cancer chemotherapy.
The development of a non-toxic selective cytoprotective agent that preferentially protects normal tissues from chemotherapy toxicity, without protecting malignant tissues, is a major challenge in cancer chemotherapy research. The available cytoprotective agents are either toxic or lack selective cytoprotective activity. Here, we report the in vitro selective cytoprotective activity of squalene, an isoprenoid molecule with antioxidant properties. Normal human bone marrow (BM) derived colony-forming unit (CFU) growth was increased by squalene in a dose-dependent manner. Squalene (12.5-25 microM) treatment significantly protected the CFUs from cisplatin-induced toxicity; the protective effect was equivalent to reduced glutathione (GSH), a known cytoprotective agent. Squalene also increased the long-term survival of cisplatin-treated 4-week-old CFUs. Cisplatin-induced apoptosis of CFUs as measured by the TUNEL assay was reduced by squalene. To examine the squalene-induced protection of tumours, several neuroblastoma cell lines, including five MYCN-amplified cell lines, were grown in monolayers, as well as in anchorage-independent cultures, in the presence of squalene and cisplatin. Squalene did not protect the neuroblastoma (NBL) cell lines from cisplatin-induced toxicity. In addition, squalene did not protect the NBL cells from carboplatin, cyclophosphamide, etoposide and doxorubicin-induced toxicity. In conclusion, our results suggest that squalene has a selective in vitro cytoprotective effect on BM-derived haematopoietic stem cells that is equipotent to GSH.
New Agent and Innovative Therapy Program, Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, Canada.
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Yeger
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Baruchel
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Freedman
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Koren
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D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy*; D013185:Squalene / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D013185:Squalene; D005978:Glutathione; D002945:Cisplatin