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Carcinogenesis Advance Access published online on May 11, 2005
Carcinogenesis, doi:10.1093/carcin/bgi121
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 11, 2005
Revised April 21, 2005
Accepted May 3, 2005

CARCINOGENESIS

Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative

Laura M. Hix 1, Dean A. Frey 2, Mark D. McLaws 2, Marianne Østerlie 3, Samuel F. Lockwood 4, and John S. Bertram 5*

1 Department of Cell and Molecular Biology, University of Hawaii at Manoa, Honolulu, HI 96822; Hawaii Biotech, Inc., Aiea, HI 96701
2 Chemical Development and Analytical Quality Services, Albany Molecular Research Inc., Albany, New York 12212
3 HIST, Department of Food Science, N-7004, Trondheim, Norway
4 Hawaii Biotech, Inc., Aiea, HI 96701
5 Department of Cell and Molecular Biology, University of Hawaii at Manoa, Honolulu, HI 96822; Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813

* To whom correspondence should be addressed.
John S. Bertram, E-mail: john{at}crch.hawaii.edu


  Abstract

Carotenoids have been implicated in numerous epidemiological studies as being protective against cancer at many sites, and their chemopreventive properties have been confirmed in laboratory studies. Astaxanthin, primarily a carotenoid of marine origin responsible for the pink coloration of salmon, shrimp and lobster, has received relatively little attention. As with other carotenoids its highly lipophilic properties complicate delivery to model systems. To overcome this issue we have synthesized a novel tetrasodium diphosphate astaxanthin (pAST) derivative with aqueous dispersibility of 25.21 mg/ml. pAST was delivered to C3H/10T1/2 cells in an aqueous/ethanol solution and compared to non-esterified astaxanthin dissolved in THF. We show it to: (1) upregulate connexin 43 (Cx43) protein expression; (2) increase the formation of Cx43 immunoreactive plaques; (3) upregulate gap junctional intercellular communication (GJIC); and (4) cause 100% inhibition of methylcholanthrene-induced neoplastic transformation at 10-6 M. In all these assays pAST was superior to non-esterified astaxanthin itself; in fact, pAST exceeded the potency of all other previously tested carotenoids in this model system. Cleavage of pAST to non-esterified (free) astaxanthin and uptake into cells was also verified by HPLC, however levels of free astaxanthin were about 100-fold lower than in cells treated with astaxanthin itself, suggesting that pAST possesses intrinsic activity. The dual properties of water dispersibility (enabling parenteral administration in vivo) and increased potency should prove extremely useful in the future development of cancer chemopreventive agents.


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