Abstract
Geranylgeranoic acid (GGA; all-trans 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid) has been shown to induce apoptosis in a human hepatoma-derived cell line, HuH-7. We aimed not only to confirm the apoptogenic properties of GGA and its derivatives, but also to search for natural GGA in medicinal herbs. GGA induced apoptosis in human hepatoma-derived cell lines, HuH-7, PLC/PRF-5, and mouse transformed hepatocyte-derived cell line, MLE-10, in a dose- and time-dependent manner, but failed to induce cell death in human hepatoblastoma-derived HepG-2 and mouse primary hepatocytes in the same condition. Besides GGA, 4,5-didehydro GGA, 14,15-dihydro GGA, and 2,3-dihydro GGA were also active to induce cell death in HuH-7 cells, while 4,5-didehydro-10,11, 14,15-tetrahydro GGA, 4,5,8,9-tetrahydro GGA, farnesoic acid, and geranylgeraniol were inert. By using liquid chromatography/mass spectrometry, we found natural GGA as a negative ion of m/z 303.4 in a Chinese herb, Schisandra chinensis, and Schisandra GGA was identified by derivatization with both mild methylation and catalytic hydrogenation. Some other GGAs hydrogenated in the different degrees, including phytanic acid (perhydro GGA), were also found in S. chinensis. GGA and phytanic acid were detected in 24 out of 25 herbs tested. The present study is the first report of natural GGA in medicinal herbs.
Highlights
Geranylgeranoic acid (GGA; all-trans 3,7,11,15tetramethyl-2,6,10,14-hexadecatetraenoic acid) has been shown to induce apoptosis in a human hepatoma-derived cell line, HuH-7
Acyclic retinoid shares characteristics of natural retinoids in vitro and in vivo [6], acyclic retinoid apparently differs from natural retinoids such as all-trans and 9-cis retinoic acids in the following respects: 1) acyclic retinoid upregulated the cellular level of albumin mRNA in human hepatoma-derived cell lines, HuH-7 and PLC/ PRF-5, while all-trans retinoic acid downregulated the expression [5]; 2) acyclic retinoid induced apoptosis in these cell lines, whereas neither all-trans nor 9-cis retinoic acid did [9]; and 3) acyclic retinoid showed no growthpromoting activity in vitamin A-deficient animals
We have reported that 4,5-didehydro geranylgeranoic acid (GGA) induced apoptosis in HuH-7 cells via downregulation of autocrine transforming growth factor-␣ expression [9]
Summary
Geranylgeranoic acid (GGA; all-trans 3,7,11,15tetramethyl-2,6,10,14-hexadecatetraenoic acid) has been shown to induce apoptosis in a human hepatoma-derived cell line, HuH-7. We have shown that the polyprenoic acid binds to cellular retinoic acid binding protein (CRABP) [3] as well as to nuclear retinoid receptors [4], exerts transcriptional activation of some hepatocyte-specific genes in hepatoma cells [5], and has preventive actions in chemical and spontaneous hepatocarcinogenesis [6,7]. We named this compound “acyclic retinoid” [8]. IPP represents the activated monomer building block for all other isoprenoids
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
