A synthetic C22 carotenoid inhibits carcinogen-induced neoplastic transformation and enhances gap junctional communication.
In 10T1/2 cells several dietary carotenoids have previously been shown to be capable of inhibiting carcinogen-induced neoplastic transformation. Two synthetic novel compounds, a C22 carotenoid, C22-polyene-tetrone-diacetal, and a C28 carotenoid, C28-polyene-tetrone, have now been tested in this system. The C22 compound was active in completely inhibiting 3-methylcholanthrene-induced transformation at 10(-5) M when added during the post-initiation phase of carcinogenesis. Gap junctional intercellular communication was strongly upregulated at this concentration. This activity has previously been shown to be highly correlated with, and has been proposed to be mechanistically linked to, inhibition of transformation by carotenoids in 10T1/2 cells. In contrast, the C28 compound, previously reported to be more active as a singlet oxygen quencher than C22, did not demonstrate activity in 10T1/2 cells in either assay system. This lack of activity was not due to chemical instability or lack of cellular uptake: the C28 compound was more stable in cell culture medium over 7 days and achieved higher cellular levels than the C22 compound (5 x 10(-11) mol/10(6) cells versus 0.5 x 10(-11) mol/10(6) cells). The activity of the C22 compound was not due to toxicity, since transformation occurred in carcinogen-treated cultures after its removal; neither was it due to antiproliferative effects on transformed cells, since the C22 compound did not prevent focus formation by transformed cells in reconstruction experiments. The demonstration that synthetic carotenoids possess biological activities comparable to the most potent naturally occurring compounds suggest that rational synthesis of compounds with improved pharmacological properties should be possible.
Molecular Oncology Unit, Cancer Research Center of Hawaii, University of Hawaii, Honolulu.
A
A
Pung
A
A
Franke
L X
LX
Zhang
H
H
Ippendorf
H D
HD
Martin
H
H
Sies
J S
JS
Bertram
D000080:Acetals / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007365:Intercellular Junctions / Q000187:drug effects / Q000502:physiology*; D007659:Ketones / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008748:Methylcholanthrene / Q000633:toxicity*; D051379:Mice; D011090:Polyenes / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
D000080:Acetals; D016588:Anticarcinogenic Agents; D007659:Ketones; D011090:Polyenes; C081442:6,10,15,19-tetramethyl-4,6,8,10,12,14,16,18,20-tetracosanonaene-2,3,22,23-tetrone; C081443:2,2,19,19-tetramethoxy-8,13-dimethyl-4,6,8,10,12,14,16-eicosaheptaene-3,18-dione; D008748:Methylcholanthrene