Reduced concentrations of serum enhance the antiproliferative activity of retinoid-related molecules and accelerate the onset of apoptosis.
Retinoid-related molecules (RRMs) that are selective agonists for the retinoic acid receptor-gamma and one retinoid antagonist are potent inducers of apoptosis in various cancer cell lines. This cell-killing activity makes them promising candidates for their use as anticancer drugs. We have observed that reducing the amount of serum in the cell culture medium significantly increased the antiproliferative activity of these RRMs in a serum concentration dependent manner. The induction of caspase activity, DNA fragmentation, and externalization of phosphatidylserine by the RRMs was markedly reduced when cells were treated in medium containing 10% serum, as compared to cells treated in low serum. High concentrations of serum also inhibited the activation of stress kinases by RRMs and higher amounts of the retinoid derivatives were necessary to cause quantitatively similar effects as compared to treatments in medium containing low serum. We have demonstrated that high concentrations of serum in the culture medium prevented the intracellular accumulation of MX3350-1 (agonist). Moreover, pre-incubation of cells in low serum-containing medium accelerated the onset of apoptosis as evidenced by the rapid activation of caspases and formation of apoptotic bodies. The release of cytochrome c and Smac induced by RRMs occurred earlier in cells that had been pre-incubated in 0.5% serum, while the activation of JNK and p38 stress kinases was unaffected.
Lopez-Hernandez
Francisco J
FJ
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA.
Ortiz
Maria A
MA
Bayon
Yolanda
Y
Piedrafita
F Javier
FJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D004987:Ethers / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D020014:K562 Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D004987:Ethers; C115167:MX 781; D012176:Retinoids; D014212:Tretinoin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases