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.