HK1110787B - Pharmaceutical composition comprising glutathione compounds and betalain for the prevention and treatment of cancer - Google Patents

Description

Reduced glutathione or certain thiol derivatives of glutathione are known to be used in combination with anthocyanins or anthocyanidins, inter alia, for the control of cancer (EP 0 545 972 B1).

It has now been found that, surprisingly, the combination of reduced glutathione or certain thiol compounds of glutathione with beta-alanes or their aglycones promises to have a much more pronounced anti-cancer effect than the previously known glutathione/anthocyanine combination, particularly if, contrary to the assumption suggested by the state of the art, the additional use or presence of anthocyanins and anthocyanidins in the combination is completely omitted.

Accordingly, a pharmaceutical composition for the purpose of the anti-cancer action is proposed according to the invention, containing as pharmaceutically active substances reduced glutathione and/or S-methylglutathione and/or S-ethylglutathione and/or S-acetylglutathione and/or S-phosphoric acid glutathione and at least one compound from the group of beta-alains and their aglycones, preferably with any other active substances not belonging to the group of anthocyanins and their aglycones.

The invention also relates to the use of reduced glutathione and/or S-methylglutathione and/or S-ethylglutathione and/or S-acetylglutathione and/or S-phosphoric acid reglutathione in combination with at least one compound from the beta-alanine group and its aglycones, preferably without the co-use of anthocyanins or their aglycones, for the therapeutic, including dietary, preventive treatment of the human or animal body against cancer.

Glutathione (gamma-glutamyl-cysteinyl-glycine) is a tripeptide of the three amino acids glutamic acid, cysteine and glycine, which is found in its reduced form (G-SH) in most human and mammalian cells.

The reduced glutathione may be replaced in whole or in part by certain thiol derivatives of glutathione in the composition of the invention, namely the mono-Methyl-Thio ester, the mono-Ethyl-Thio ester, the mono-Acetyl-Thio ester and/or the mono-Phosphoric acid-Thio ester of glutathione.

Thiol derivatives of glutathione have the advantage of higher bioavailability over reduced glutathione in some applications because of their high ability to permeate biological membranes and because they protect the SH group of glutathione, which is important for its therapeutic effect, on its path through the biological compartments to the desired site of action.

Alternatively to or alongside the thiol derivatives of glutathione, certain glutathione esters, where esterification occurs not at the thiol group but at the carboxyl group of the glycyl residue, are also suitable: mono-methylglutathione ester, mono-ethylglutathione ester, mono-acetylglutathione ester, mono-phosphoric acid reglutathione ester and/or isopropylglutathione ester. These derivatives are also more lipophilic than G-SH and can therefore permeate better into cell membranes.

Betalains are flower and fruit dyes derived from batalamic acid. They include the red-violet betacyanins from red beets (Beta vulgaris) and the yellow betaxanthines from cacti. Typical representatives of the betacyanins are betanin, isobetanin, prebetanin and isoprebetanin. The aglycon of the betanin is the betanidin. Typical representatives of the betaxanthines are vulgarxanthin I and vulgarxanthin II. The betacyanins are obtained primarily by isolation from the corresponding flowers and fruits; through various tests they can be clearly distinguished from the isocyanins, see Antwerp, Nature's Handbook of the Precursors.

According to the invention, a composition is preferred with reduced glutathione and/or S-acetylglutathione and betanin and/or betanidin as active ingredients. A process for the production of S-acetylglutathione has been published in the US 2,760,956. Betanin, also called beet red (C24H26N2O13), is approved as a food and cosmetic dye and is obtained from beet.

The composition of the invention may contain as additional active substances FAD (flavin adenine dinucleotide) and/or genistein, e.g. derived from soybeans.

Superoxide dismutase (SOD) is particularly suitable as an additional active substance in the composition of the invention, preferably at a daily dose of 500 mg to 1500 mg.

The composition of the invention can be used for all types of cancer and metastases, in oral, nasal, baccal or sublingual application, as an injection, as an infusion or as a suppositorium.

Such carriers can be used to reduce the toxicity of the active substances in a known way and increase their effectiveness by directed release at the exact site of the tumour or metastasis.

In vitro studies on the effects of reduced glutathione (G-SH) and anthocyanins and betacyanins, individually and in different combinations, on tumour cell lines, namely H69: human small cell lung cancer, were performed using G-SH and betalaine as a dry extract of beta vulgaris (product of Sprüh-Atom Schumann & Sohn GmbH, Karlsruhe), and as a comparator, anthocyanins as dry extracts of Cassis (black currants) and Vaccinium (heidelberries). The tumour cell lines were repeated in vitro with 10% FCS. The final concentration of the administered subtotal of GSHS, Vaccinium, and Vaccinium was significantly increased without the presence of apoptosis. The effect was also significantly greater on both the tablets and the test tube (after a single treatment) than on the tablets with H69 and Vaccinium. The number of antibodies was also significantly increased in the controlled test.

A typical anticancer drug based on the invention is available in the form of tablets for oral use, each containing 200 mg glutathione and 200 mg betatom as the only active ingredients, given at a dose of 5 to 10 tablets per day.

Apoptotic and defective H69 tumour cells after 10 days of treatment

apoptotische Zellen (%Gesamtzellen)	21,9	26,5	28,7	48,9	34,6	35,4	63,0	65,6	66,7	86,6	27,3
Veränderung gegenüber Kontrolle (%)	-5	-0,7	1,4	21,7	8,2	7,4	35,8	38,4	39,5	59,3
defekte Zellen (%Gesamtzellen)	37,9	45,2	45,4	58,0	51,3	54,3	61,0	68,7	72,5	88,9
Veränderung gegenüber Kontrolle (%)	8,9	16,2	16,3	28,9	22,2	25,2	32,0	39,6	43,5	59,8

Claims (9)

1. A pharmaceutical composition for the prevention and control of cancer, containing, as pharmaceutically active substances, reduced glutathione and/or S-methyl glutathione and/or S-ethyl glutathione and/or S-acetyl glutathione and/or S-phosphoric glutathione and/or monomethyl glutathione ester and/or monoethyl glutathione ester and/or monoacetyl glutathione ester and/or monophosphoric glutathione ester and/or isopropyl glutathione ester, and at least one compound of the group consisting of the betalaines and the aglycones thereof.
2. The pharmaceutical composition as claimed in claim 1, wherein any other active substances it may include do not belong to the group of anthocyan and the aglycones thereof.
3. A pharmaceutical composition for the prevention and control of cancer, containing, as pharmaceutically active substances, exclusively reduced glutathione and/or S-methyl glutathione and/or S-ethyl glutathione and/or S-acetyl glutathione and/or S-phosphoric glutathione, as well as at least one compound of the group consisting of the betalains and the aglycones thereof.
4. The composition as claimed in claim 2 or 3, containing, as pharmaceutically active substances, reduced glutathione and/or S-methyl glutathione and/or S-ethyl glutathione and/or S-acetyl glutathione and/or S-phosphoric glutathione, as well as at least one compound of the group consisting of betacyans and the aglycones thereof.
5. The composition as claimed in claim 4, containing reduced glutathione and/or S-acetyl glutathione as well as betanin and/or betanidin.
6. The composition as claimed in claim 1, 2, 4, or 5, containing superoxide dismutase as a further pharmaceutically active substance.
7. The composition as claimed in any one of claims 1 to 6, wherein the pharmaceutically active substance is included completely or partly in liposomes and/or cyclodextrins as molecular substrates.
8. Use of a pharmaceutical composition as claimed in any one of claims 1 to 7 or the pharmaceutically active substances thereof in combination with one another for treating a human or animal body against cancer.
9. The use as claimed in claim 8 without including the use of anthocyans and the aglycones thereof.