Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth.
Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.
Das
Bikul
B
Developmental Biology and Stem Cell Program, Research Institute, The Hospital for Sick Children, Toronto, Canada. bikul.das@utoronto.ca
Antoon
Roula
R
Tsuchida
Rika
R
Lotfi
Shamim
S
Morozova
Olena
O
Farhat
Walid
W
Malkin
David
D
Koren
Gideon
G
Yeger
Herman
H
Baruchel
Sylvain
S
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D019610:Cytoprotection / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D013185:Squalene / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000975:Antioxidants; D013185:Squalene; D016190:Carboplatin; D002945:Cisplatin