Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-11
2004-03-30
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S452000, C514S454000, C514S455000, C514S456000, C514S457000, C514S458000, C514S461000, C514S470000, C514S471000, C514S472000, C514S473000, C514S513000, C514S529000, C514S532000
Reexamination Certificate
active
06713506
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to polyphenol esters derived from green and black teas, and analogs thereof, which are potent inhibitors of the growth of cancerous cells. Specifically, the invention relates to polyphenol esters that inhibit chymotrypsin-like, but not trypsin-like, proteasome activity, whereby tumor cells are arrested in G
1
phase and selective apoptosis of cancerous cells is promoted. Therefore, the invention relates to novel polyphenol esters and their use in the prevention and treatment of conditions characterized by abnormal cellular proliferation.
BACKGROUND OF THE INVENTION
Previous studies have suggested that tea consumption may have a protective effect against human cancer (Fujiki, 1999,
J Cancer Res Clin Oncol
125:589-97; Kuroda et al., 1999,
Mutat Res
436:69-97; Yang, 1999,
Nutrition
15:946-9; Ahmad et al., 1999,
Nutr Rev
57:78-83). The major components of green and black tea include epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG), epicatechin (EC), and their epimers (see FIG.
1
A).
Although tea-derived polyphenols affect numerous cancer-related proteins and have been shown to have anti-tumor property, their precise molecular targets have not been identified. The ubiquitin-proteasome system plays a critical role in the specific degradation of cellular proteins (Hochstrasser, 1995,
Curr Opin Cell Biol
7:215-23), and one of the proteasome's functions is to protect tumor cells against apoptosis (Dou et al., 1999,
Drug Resistance Updates
2:215-223). The chymotrypsin-like, but not trypsin-like, activity of the proteasome is associated with tumor cell survival (An et al., 1998,
Cell Death Differ
5:1062-75; Lopes et al., 1997,
J Biol Chem
272:12893-6).
The absence of specific knowledge of the molecular targets of tea-derived compounds having antitumor activities or activities directed against proliferative diseases has slowed development of more potent and specific analogs. Specifically, identification of the molecular target proteins of tea-derived compounds would facilitate development of better inhibitors through molecular modeling of the inhibitor-binding site.
Similarly, the absence of knowledge of the chemical features of such tea-derived compounds that are required for biological activity has also slowed development of improved analogs. In addition, knowledge of the specific targets of such tea-derived compounds permits rational design of cancer therapy and prevention strategies, where simultaneous manipulation of multiple metabolic pathways may be desirable.
SUMMARY OF THE INVENTION
As disclosed herein for the first time, the present invention provides means to address these problems. Herein, it is disclosed how ester-bond containing tea polyphenols potently inhibit the proteasomal chymotrypsin-like activity in vivo and in vitro. Treatment with tea-derived polyphenols is herein correlated with accumulation of cellular levels of both p27
KiP1
and I&kgr;B-&agr; two natural proteasome substrates, and G
1
-phase arrest of tumor cells.
In one embodiment, the present invention provides a method for inhibiting the proteasomal chymotrypsin activity. The inventive method comprises contacting the cell with an effective amount of a polyphenol ester having an ester bond that has a susceptibility to nucleophilic attack. Significantly, the method according to this invention does not inhibit the proteasomal trypsin activity in a cell. According to a preferred embodiment, the method of the present invention uses a tea-derived polyphenol compound, particularly, the polyphenol compound such as EGCG, ECG, GCG, or CG. According to another preferred embodiment, the polyphenol compound suitable for the instant invention is selected from the group consisting of formulae 1-29, as herein below described.
In another embodiment, the present invention provides for a method for treating or preventing cancer in a patient, comprising administering to the patient an effective amount of a polyphenol ester having an ester bond that has a susceptibility to nucleophilic attack. The inventive method is effective against major cancer types such as prostate cancer, breast cancer, lung cancer, colorectal cancer, bladder cancer, non-Hodgkin's lymphoma, uterine cancer, melanoma of the skin, kidney cancer, liver cancer, leukemia, ovarian cancer, and pancreatic cancer.
In yet another embodiment, the present invention discloses analogs of tea-derived polyphenols. Preferably, the analogs of tea-derived polyphenols of the present invention have the structure of formulae 1-28.
All these features and benefits of the present invention will become apparent to those of skill in the art upon reading the following disclosure.
REFERENCES:
patent: 5104901 (1992-04-01), Shimamura et al.
patent: 5804567 (1998-09-01), Cheng et al.
Ahmad, S. et al. “Green Tea Ployphenol Epigallocatechin-3-gallate Inhibits the IL-1&bgr;-induced Activity and Expression of Cyclooxygenase-2 and Nitric Oxide Synthase-2 in Human Chondrocytes”Free Redical Biology and Medicine, 2002, vol. 33, No. 8, pp. 1097-1105.
An, B. et al. “Novel Dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts”Cell Death and Differentiation, 1998, vol. 5, pp. 1062-1075.
Balasubramanian, S. et al. “Green Tea Polyphenol Stimulates a Ras, MEKK1, MEK3, and p38 Cascade to Increase Activator Protein 1 Factor-dependent Involucrin Gene Expression in Normal Human Keratinocytes”The Journal of Biological Chemistry, Jan. 18, 2002, vol. 277, No. 3, pp. 1828-1836.
Balentine, D. et al. “The Chemistry of Tea Flavonoids”Critical Reviews in Food Science and Nutrition, 1997, vol. 37, No. 8, pp. 693-704.
Baumeister, W. et al. The Proteasome: Paradigm of a Self-Compartmentalizing Protease,Cell, Feb. 6, 1998, vol. 92, pp. 367-380.
Chen, Z. et al. “Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts”Cancer Letters, 1998, vol. 129, pp. 173-179.
Dick, L. et al. “Mechanistic Studies on the Inactivation of the Proteasome by Lactacystin”The Journal of Biological Chemistry, Mar. 29, 1996, vol. 271, No. 13, pp. 7273-7276.
Fenteany, G. et al. “Inhibition of Proteasome Activities and Subunit-Specific Amino-Terminal Threonine Modification by Lactacystin”Science, May 5, 1995, vol. 268, pp. 726-731.
Fenteany, G. et al. “Lactacystin, Proteasome Function, and Cell Fate”The Journal of Biological Chemistry, Apr. 10, 1998, vol. 273, No. 15, pp. 8545-8548.
Fujiki, H. et al., “Green tea: cancer preventative beverage and/or drug”Cancer Letters, 2002, vol. 188, pp. 9-13.
Fujiki, H. et al. “Two stages of cancer prevention with green tea”J Cancer Res Clin Oncol, 1999, vol. 125, pp. 589-597.
Gazos Lopes, U. et al. “p53-dependent Induction of Apoptosis by Proteasome Inhibitors”The Journal of Biological Chemistry, May 16, 1997, vol. 272, No. 20, pp. 12893-12896.
Groll, M. et al. “Structure of 20S proteasome from yeast at 2.4A resolution”Nature, vol. 386, Apr. 3, 1997, pp. 463-471.
Gupta, S. et al. “Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols”PNAS, Aug. 28, 2001, vol. 98, No. 18, pp. 10350-10355.
Guttridge, D. et al. NF-kB Controls Cell Growth and Differentiation through Transciptional Regulation of Cyclin D1”Molecular and Cellular Biology, Aug. 1999, pp. 5785-5799.
Heinemeyer, W. et al. “The Active Sites of the Eukaryotic 20 S Proteasome and the Involvement of Subunit Precursor Processing”The Journal of Biological Chemistry, Oct. 3, 1997, vol. 272, No. 40, pp. 25200-25209.
Hinz, M. et al. “NF-kB Function in Growth Control: Regulation of Cyclin D1 Expression and G0/G1-to-S-Phase Transition”Molecular and Cellular Biology, Apr. 1999, vol. 19, No. 4, pp. 2690-2698.
Hiipakka, R. et al. Structure-activity relationships for inhibition of human 5a-reductases by polyphenolsBiochemical Pharmocology, 2002, vol. 63, pp. 1165-1176.
Jodoin, J. et
Dou Q. Ping
Nam Sangkil
Smith David M.
Covington Raymond
Rotman Alan L.
Saliwanchik Lloyd & Saliwanchik
University of South Florida
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