[Effect of d-limonene, Salvia miltiorrhiza and turmeric derivatives on membrane association of Ras gene product and gap junction intercellular communication].
Gap junction intercellular communication (GJIC), H-ras oncogene expression and Ras oncogene product(P21ras protein) expression were studied in four human solid tumor cell lines, W1-38, CACO2, A549 and PaCa (with the different Ras gene mutation rate), and the effects of four compounds, Salvia miltiorrhiza derivative (SMD), d-limonene, turmeric derivative I(TD-I) and turmeric derivative II(TD-II), on them. The abilities of the four solid tumor cell lines to transfer dye to adjacent cells were examined using the scrape-loading/dye transfer technique, and the H-ras oncogene expression by Northern blotting and P21ras protein expression by Western blotting. The results showed the loss of intercellular coupling in PaCa cells, slight GJIC in A549 and CACO2 cells, and good GJIC in W1-38 cells. The four compounds used was shown to improve the GJIC of PaCa to different extents. The amount of total and membrane associated P21ras in PaCa cells were decreased after treatment with SMD, d-limonene and TD-I(2.5 micrograms.ml-1) for 48 h. Concomitantly, the growth of PaCa cells decreased in soft agar and GJIC was enhanced. The relative potency was found to be: d-limonene > SMD > TD-I = TD-II. No significant effect of the four compounds on H-ras oncogene expression was observed. These results suggest that 1. there was an excellent correlation between loss of Lucifer Yellow dye transfer and ras gene mutation rate in the four solid tumor cell lines used (ras gene mutation rate inversely correlated with average cell number couplied, r = 0.98) i.e., showing that high ras gene mutation is closely correlated with loss of GJIC in these malignant human tumor cells; 2. the antitumor effect of the monoterpene d-limonene and the phenol compound, SMD, might be related to the inhibition of P21ras membrane association and enhancement of GJIC, whilst that of the others may be by a different mechanism; 3. the inhibition of P21ras membrane association is directly related to the enhancement of gap junction intercellular communication.
Chen
X
X
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050.
Shuzo
O
O
Li
Y
Y
Han
R
R
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D030024:Curcuma / Q000737:chemistry; D053138:Cyclohexenes; D017629:Gap Junctions / Q000473:pathology; D015870:Gene Expression; D011905:Genes, ras; D006801:Humans; D000077222:Limonene; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis*; D010936:Plant Extracts / Q000494:pharmacology*; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013729:Terpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D053138:Cyclohexenes; D010936:Plant Extracts; D013729:Terpenes; C012596:turmeric extract; D000077222:Limonene; D015689:Oncogene Protein p21(ras)