Abstract
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.
Highlights
For many centuries, a plethora of natural products have been used in traditional medicine for the treatment of numerous ailments
As we have previously found PST (Figure 1A) to be effective in producing cytotoxicity selectively in various cancer cell lines, we evaluated the activity of JCTH-4 (Figure 1B) in the OS cell lines Saos-2 and U-2 OS using the WST-1 based colorimetric assay for cell viability
human osteoblasts (HOb) cells are the non-cancerous counterpart to the OS cell lines used in this study, we evaluated the toxicity of this compound on another non-transformed non-cancerous human fetal fibroblast cell line (NFF) to confirm the selective anti-cancer activity of this compound
Summary
A plethora of natural products have been used in traditional medicine for the treatment of numerous ailments. One such product includes the Curcuma longa herb [1]. This herb has been used to treat anorexia, rheumatism, sinusitis, hepatic disorders, and inflammation [2]. A component of this herb, the compound curcumin (CC) referred to as (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione or diferuloylmethane, has been recognized for its antiproliferative properties in treating cancer [1]. The anti-neoplastic properties of CC are exhibited in many types of malignancies including breast cancer, colon cancer, kidney cancer, leukemia, prostate cancer, melanoma, and osteosarcoma (OS) [1,4]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
