Liposomal short-chain C6 ceramide induces potent anti-osteosarcoma activity in vitro and in vivo.
Osteosarcoma (OS) remains one deadly disease for many affected patients. The search for novel and more efficient anti-OS agents is urgent. In the current study, we demonstrated that liposome-packed C6 ceramide exerted potent cytotoxic effect against established (U2OS and MG-63 lines) and primary human OS cells. Meanwhile, the liposomal C6 (ceramide) induced caspase-mediated apoptotic death in OS cells. Liposomal C6 was significantly more potent than conventional free C6 in inhibiting OS cells, yet it was safe to non-cancerous bone cells (primary murine osteoblasts or human MLO-Y4 osteocytic cells). At the signaling level, we showed that liposomal C6 potently inhibited Akt activation in OS cells. Further studies revealed that a low dose of liposomal C6 dramatically sensitized the in vitro anti-OS activity of two conventional chemodrugs: methotrexate (MTX) and doxorubicin. In vivo, intravenous injection of liposomal C6 inhibited Akt activation and suppressed U2OS xenograft growth in nude mice without causing apparent toxicities. Meanwhile, when given at a low-dose (5 mg/kg body weight), liposomal C6 dramatically sensitized MTX's anti-U2OS activity in vivo. Collectively, our data demonstrate that liposomal C6 exerts potent anti-tumor activity in preclinical OS models.
Department of Orthopaedic Surgery, The Affiliated Hospital of Logistics College of Chinese People's Armed Police Force, Tianjin, China.
Lei
L
Zhai
Department of Nephropathy, The Affiliated Hospital of Logistics College of Chinese People's Armed Police Force, Tianjin, China.
Nan
N
Sun
Department of Orthopaedic Surgery, Tianjin Hospital, Tianjin, China.
Zhe
Z
Han
Department of Orthopaedic Surgery, The Affiliated Hospital of Logistics College of Chinese People's Armed Police Force, Tianjin, China.
Hai-chao
HC
Jin
Department of Immunology, Tianjin Medical University, Tianjin, China. Electronic address: tianjinzhang889@163.com.
Bo
B
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008081:Liposomes; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002518:Ceramides; D008081:Liposomes; C101954:N-caproylsphingosine; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D008727:Methotrexate
Akt; Apoptosis; Liposomal C6 ceramide; Methotrexate and chemo-sensitization; Osteosarcoma