Inhibition of tumor growth by S-3-1, a synthetic intermediate of salvianolic acid A.
Salvianolic acid A (1) is one of the active components from Salvia miltiorrhiza, which was found to suppress the growth of mouse tumors. S-3-1 (a 2-allyl-3,4-dihydroxybenzaldehyde, 2) is a synthetic intermediate of a salvianolic acid A derivative with strong inhibitory effects on the growth of cancer cells in vitro. The inhibitory effects of 2 on tumor growth and its molecular targets were studied. 2 significantly suppressed the growth of mouse Lewis lung carcinoma, S180 sarcoma and H22 hepatic carcinoma in a dose-dependent manner. With a simple scrape-loading dye transfer method, 20 microg/ml of 2 was found to significantly enhance gap junction intercellular communication (GJIC) in human pancreatic adenocarcinoma PaCa Cells, human lung epithelial carcinoma W1-38 cells and human lung adenocarcinoma A549 cells, but 2 had no marked effect on GJIC in human colon cancer CACO2 cells. With Northern blot analysis, 2 was found to inhibit the expression of c-myc gene in A549 cells and have no marked effect on H-ras oncogene expression, and increase the cellular P53 mRNA contents, though it did not affect the expression of RB tumor suppressor gene. 2 also suppressed the P46 (JNK/SAPK) expression in A549 cells. Western blot analysis was applied to visualize the P21ras protein. Results shows that 2 at concentrations ranging from 10 to 20 microg/ml decreases the contents of the membranous P21ras and total P21ras and increases the contents of cytosolic P21ras protein in a time-dependent manner. However, 2 had no significant effects on farnesyl protein transferase activities at the concentrations that could efficiently decrease the membranous P21ras content. This suggested that 2 might suppress tumor growth partly through enhancement of GJIC and reversion of the transformed phenotypes. The other mechanisms may be that 2 can suppress the overexpression of c-myc oncogene, inhibit the function of Ras oncoprotein, increase the expression of P53 tumor suppressor gene and interrupt P46-associated mitogen-activated pathway other than farnesylation of Ras protein.
Li
Hong-Yan
HY
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Li
Yan
Y
Yan
Chun-Hong
CH
Li
Lian-Niang
LN
Chen
Xiao-Guang
XG
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D001547:Benzaldehydes / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D018938:Caco-2 Cells; D002109:Caffeic Acids / Q000737:chemistry*; D002396:Catechols / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020570:Genes, myb; D016158:Genes, p53; D006801:Humans; D007773:Lactates / Q000737:chemistry*; D008113:Liver Neoplasms / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008934:Mitogens; D010641:Phenotype; D012509:Sarcoma / Q000473:pathology; D014407:Tumor Cells, Cultured
C473379:2-allyl-3,4-dihydroxybenzaldehyde; D000498:Allyl Compounds; D001547:Benzaldehydes; D002109:Caffeic Acids; D002396:Catechols; D007773:Lactates; D008934:Mitogens; C005581:protocatechualdehyde; C066201:salvianolic acid A