Selective cytotoxicity against human osteosarcoma cells by a novel synthetic C-1 analogue of 7-deoxypancratistatin is potentiated by curcumin

• Published in: PloS one 2011-12, Vol.6 (12), p.e28780
• Main Authors: Ma, Dennis, Tremblay, Phillip, Mahngar, Kevinjeet, Collins, Jonathan, Hudlicky, Tomas, Pandey, Siyaram
• Format: Article
• Language: English
• Subjects: Acetic acid; Amaryllidaceae Alkaloids - chemistry; Amaryllidaceae Alkaloids - pharmacology; Analogs; Analogue; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; Autophagy; Biochemistry; Biocompatibility; Biology; Biomedical materials; Bone cancer; Cancer; Cancer therapies; Cell death; Cell Line, Tumor; Chemistry; Chemotherapy; Colorectal cancer; Curcumin; Curcumin - pharmacology; Cytotoxicity; Dose-Response Relationship, Drug; Drug resistance; Drug Synergism; Endonuclease; Fetuses; Fibroblasts; Genotoxicity; Humans; Isoquinolines - chemistry; Isoquinolines - pharmacology; Kinases; Leukemia; Medical prognosis; Medicine; Melanoma; Membrane potential; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; New combinations; Osteoblasts; Osteosarcoma; Osteosarcoma - pathology; Osteosarcoma cells; Oxygen; Phagocytosis; Prostate; Reactive oxygen species; Sarcoma; Selectivity; Synthesis; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028780

The natural compound pancratistatin (PST) is a non-genotoxic inducer of apoptosis in a variety of cancers. It exhibits cancer selectivity as non-cancerous cells are markedly less sensitive to PST. Nonetheless, PST is not readily synthesized and is present in very low quantities in its natural source to be applied clinically. We have previously synthesized and evaluated several synthetic analogues of 7-deoxypancratistatin, and found that JC-TH-acetate-4 (JCTH-4), a C-1 acetoxymethyl analogue, possessed similar apoptosis inducing activity compared to PST. In this study, notoriously chemoresistant osteosarcoma (OS) cells (Saos-2, U-2 OS) were substantially susceptible to JCTH-4-induced apoptosis through mitochondrial targeting; JCTH-4 induced collapse of mitochondrial membrane potential (MMP), increased reactive oxygen species (ROS) production in isolated mitochondria, and caused release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from isolated mitochondria. Furthermore, JCTH-4 selectively induced autophagy in OS cells. Additionally, we investigated the combinatory effect of JCTH-4 with the natural compound curcumin (CC), a compound found in turmeric spice, previously shown to possess antiproliferative properties. CC alone had no observable effect on Saos-2 and U-2 OS cells. However, when present with JCTH-4, CC was able to enhance the cytotoxicity of JCTH-4 selectively in OS cells. Such cytotoxicity by JCTH-4 alone and in combination with CC was not observed in normal human osteoblasts (HOb) and normal human fetal fibroblasts (NFF). Therefore, this report illustrates a new window in combination therapy, utilizing a novel synthetic analogue of PST with the natural compound CC, for the treatment of OS.