Evaluation of the mammalian target of rapamycin pathway and the effect of rapamycin on target expression and cellular proliferation in osteosarcoma cells from dogs

Abstract

These data indicated that mTOR and its downstream product are present and active in canine osteosarcoma cells. The pathway can be inhibited by rapamycin, and treatment of cells with rapamycin decreased the surviving tumor cell fraction. These data support the molecular basis for further investigation into the use of mTOR inhibitors as an antineoplastic approach for dogs with osteosarcoma.

Immunohistochemical Analysis of the Akt/mTOR/4E-BP1 Signalling Pathway in Canine Haemangiomas and Haemangiosarcomas

“…In dogs, activation of this pathway has been reported only in cell lines derived from cases of melanoma (Kent et al, 2009) and osteosarcoma (Gordon et al, 2008). In canine HSA, a mutation of PTEN, a down-regulator of PI3K activity, has been reported (Dickerson et al, 2005).…”

“…7). Rapamycin, an inhibitor of mTORC1, has been evaluated in canine osteosarcoma (Gordon et al, 2008) and melanoma cell lines (Kent et al, 2009), and these studies have indicated anti-tumour effects of rapamycin. The present findings imply that an inhibitor of mTORC1 may not have a strong anti-tumour effect in canine HSAs.…”

The importance of the PI3K/AKT/mTOR signaling pathway in canine neoplasms: Literature review

“…This study demonstrated the pathway activation for all studied lines and showed that Rapamycin was able to inhibit mTOR activity. The clonogenic assay demonstrated how effectively this inhibitor reduces survival of tumor cells exposed to the drug, suggesting that this can have a beneficial effect on canine osteosarcoma cells (Gordon et al 2008).…”

Targets for cancer therapy in childhood sarcomas

“…mTOR activation as assessed by its phosphorylation has been detected among all childhood sarcoma entities discussed here and was negatively correlated with rhabdomyosarcoma survival (54-56). Inhibition of mTOR by Rapamycin or derivatives thereof inhibited proliferation of childhood sarcoma cells in vitro (55,57,58) and also inhibited the growth of xenografts of rhabdomyosarcoma and osteosarcoma cell lines in vivo (58,59). In vitro the mechanisms of action has been reported to dependent on the p53/p21 status.…”

“…It is therefore reasonable to assume that, in addition to improved survival rates achieved with conventional chemotherapeutics in the last 30 years, a further increase in survival rates for many childhood malignancies lies ahead of us with hopefully simultaneous decrease of side effects. [187] Notch [188] MUC18 [189] CTLA-4 [190] Hedgehog [191] Intracellular signaling molecules mTor [57-59] PDK-1/AKT [175] Src [176] Mek/Erk [177][178] Estrogen receptor [179] Mirk/Dyrk1B [180] Smad4 [181] Retinoic acid [182] mTOR [58] Src [176] Lyn [186] mTor [55,58] c-jun [192][193] Src [176,198] Stathmin [194][195] α-CaMKII [196] Cell cycle Targets discussed in the text are written in bold. …”