Betulinic acid treatment promotes apoptosis in hepatoblastoma cells.
Hepatoblastoma (HB) represents the most common malignant liver tumor in children with a dismal prognosis for patients with advanced disease. This study provides evidence that the naturally occurring pentacyclic triterpenoid betulinic acid (BA) is highly effective against HB. We demonstrate that BA has a strong cytotoxic effect on HB cells in a dose-dependent manner by impinging on cell viability and causing massive induction of programmed cell death. Apoptotic features including morphological changes, membrane asymmetry and proteolytic cleavage of caspase 3 and poly(ADP-ribose) polymerase were frequently found in BA-treated HB cells, which is suggestive of the mitochondrial intrinsic apoptotic pathway. In contrast, the hepatocellular carcinoma (HCC) cell line HepG2 was resistant to BA treatment. This insensitivity was dependent on the high expression of survival factors, such as Survivin and BCL2. Interestingly, BA treatment led to a significant decrease in expression of the hedgehog target genes GLI1, PTCH1 and IGF2 in HepT3 cells. In conclusion, we demonstrate that BA is capable of inducing apoptosis in HB cells and thereby might be a hopeful new strategy for treating HB, especially those with an activated hedgehog signaling pathway.
Eichenmüller
M
M
Department of Pediatric Surgery, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, 80337 Munich, Germany.
von Schweinitz
D
D
Kappler
R
R
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D014157:Transcription Factors / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000071676:Zinc Finger Protein GLI1; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D053823:Hedgehog Proteins; D051034:Inhibitor of Apoptosis Proteins; D007335:Insulin-Like Growth Factor II; D008869:Microtubule-Associated Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D000077022:Survivin; D014157:Transcription Factors; D014315:Triterpenes; D000071676:Zinc Finger Protein GLI1; D000094062:Betulinic Acid; C107489:BIRC5 protein, human; C400551:GLI1 protein, human; C035170:IGF2 protein, human; C000606236:PTCH1 protein, human; C505407:CASP3 protein, human