WO2018015776A1 - Composition basée sur l'action synergique de l'acide lipoïque et de la sélénite et son utilisation pour la prévention et le traitement de troubles néoplasiques - Google Patents
Composition basée sur l'action synergique de l'acide lipoïque et de la sélénite et son utilisation pour la prévention et le traitement de troubles néoplasiques Download PDFInfo
- Publication number
- WO2018015776A1 WO2018015776A1 PCT/HU2017/050013 HU2017050013W WO2018015776A1 WO 2018015776 A1 WO2018015776 A1 WO 2018015776A1 HU 2017050013 W HU2017050013 W HU 2017050013W WO 2018015776 A1 WO2018015776 A1 WO 2018015776A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- selenite
- sodium
- acid
- lipoic acid
- alpha
- Prior art date
Links
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 200
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 155
- 239000000203 mixture Substances 0.000 title claims abstract description 123
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 56
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 title claims abstract description 36
- 229940082569 selenite Drugs 0.000 title claims abstract description 33
- 238000011282 treatment Methods 0.000 title claims description 29
- 230000001613 neoplastic effect Effects 0.000 title claims description 11
- 230000002265 prevention Effects 0.000 title claims description 9
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 title abstract 2
- 239000013543 active substance Substances 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 239000003085 diluting agent Substances 0.000 claims abstract description 5
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims description 195
- 229960001471 sodium selenite Drugs 0.000 claims description 165
- 239000011781 sodium selenite Substances 0.000 claims description 165
- 235000015921 sodium selenite Nutrition 0.000 claims description 157
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical group [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 claims description 156
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims description 39
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 20
- 229930182832 D-phenylalanine Natural products 0.000 claims description 20
- 239000001903 2-oxo-3-phenylpropanoic acid Substances 0.000 claims description 19
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 19
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 19
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 claims description 19
- 229930182827 D-tryptophan Natural products 0.000 claims description 18
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 claims description 18
- 229930195722 L-methionine Natural products 0.000 claims description 18
- 229960004452 methionine Drugs 0.000 claims description 18
- BTNMPGBKDVTSJY-UHFFFAOYSA-N keto-phenylpyruvic acid Chemical compound OC(=O)C(=O)CC1=CC=CC=C1 BTNMPGBKDVTSJY-UHFFFAOYSA-N 0.000 claims description 15
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 claims description 7
- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 claims description 7
- DEDGUGJNLNLJSR-UHFFFAOYSA-N alpha-hydroxycinnamic acid Natural products OC(=O)C(O)=CC1=CC=CC=C1 DEDGUGJNLNLJSR-UHFFFAOYSA-N 0.000 claims description 7
- 229960005219 gentisic acid Drugs 0.000 claims description 7
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 claims description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- NGSWKAQJJWESNS-UHFFFAOYSA-N 4-coumaric acid Chemical compound OC(=O)C=CC1=CC=C(O)C=C1 NGSWKAQJJWESNS-UHFFFAOYSA-N 0.000 claims description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 6
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- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 3
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- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 3
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 3
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- 229930028154 D-arginine Natural products 0.000 claims description 3
- 239000011665 D-biotin Substances 0.000 claims description 3
- 235000000638 D-biotin Nutrition 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 3
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- 229960005305 adenosine Drugs 0.000 claims description 3
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- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical group C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
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- SPVXKVOXSXTJOY-UHFFFAOYSA-N selane Chemical compound [SeH2] SPVXKVOXSXTJOY-UHFFFAOYSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- composition based on the synergistic action of lipoic acid and selenite and use thereof for the prevention and treatment of neoplastic disorders
- the subject matter of the invention is a composition containing lipoic acid and selenite and a mixture of certain small molecules, applied for the prevention and treatment of neoplastic disorders.
- Alpha-lipoic acid is an endogenous, disulfide bridge-containing short chain fatty acid.
- the basic biological function of alpha-lipoic acid is that it is the cofactor of certain mitochondrial multi-enzyme complexes such as the pyruvate-dehydrogenase enzyme complex through which it has an important role in the decarboxylation of alpha-ketoacids and thus in the mitochondrial energy production.
- the alpha-lipoic acid contains one chiral carbon atom, of its stereoisomers the R-enantiomer is the biologically active form as a cofactor of the above mentioned enzyme complex.
- the alpha-lipoic acid is a strong antioxidant [1] and utilizing this property it is applied as a pharmaceutical in the treatment of diabetic neuropathy.
- Both the alpha-lipoic acid and its reduced form the dihydrolipoic acid have been shown to be able to capture reactive oxygen species (e.g. hydroxyl radicals, superoxide radicals, hypochlorous acid) and to form complexes with the ions of various transition metals [2-4]. It has been shown that the alpha-lipoic acid is able to increase the level of reduced glutathione which is an important intracellular antioxidant molecule [5].
- alpha-lipoic acid causes cell death in various cancer cell lines (Jurkat, H460, MCF-7 etc.) [6-10].
- treatment with alpha-lipoic acid increases the production of superoxide anions in the mitrochondria, decreases the amount of anti-apoptotic proteins (bcl-2, bcl-xl), induces cytochrome c release from the mitochondria, activates caspase-9 and PARP-1, cumulatively induces the activation of the mitochondrial pathway of apoptosis in cancer cells [6, 7, 11].
- caspase-independent cell death and autophagy also may have a role in the anti-cancer effect of alpha-lipoic acid [12, 13].
- the treatment with alpha-lipoic acid is also capable to inhibit the PBK-Akt-mTOR cascade which is an important oncogenic signaling pathway.
- Treatment with alpha-lipoic acid reduces both the total amount of Akt protein and the level of phosphorylated Akt [14].
- the alpha-lipoic acid has been shown to increase the anti-tumor effect of certain cytostatics (5-fluorouracil, etoposide) [12, 15].
- Selenium is an essential trace element, with the main biological function of being incorporated into selenoproteins and through the oxidoreductase activity of such proteins it contributes to the maintenance of the proper redox state of the cell [21]. On the basis of this selenium can be considered as an indirect antioxidant.
- Selenium is present in foodstuffs in the form of different organic compounds: selenomethionine (SeMet), selenocysteine (SeCys), seleno-methyl-selenocysteine (SMSC); while in the soil it occurs mainly in the form of selenate and selenite.
- the above mentioned compounds can be considered as redox-active, since in the presence of reduced glutathione, on the one hand as substrates of oxidoreductase enzymes they can be transformed to hydrogen selenide, accompanied by the production of reactive oxygen species, on the other hand selenide anions can be produced through a redox-cycle, also accompanied by the production of reactive oxygen species [22-24]. Numerous redox-active organic and inorganic selenium compounds have been shown to possess some degree of antitumor activity [25].
- selenite anion of selenous acid
- Selenite has been shown to influence numerous signal transduction pathways which have vital importance for cancer cells: in addition to the production of reactive oxygen species mentioned above, selenite is able to induce apoptosis through the inhibition of the Akt pathway, it is able to shift autophagy toward apoptosis through the inhibition of the Nfkappab pathway, additionally it can also induce caspase-independent cell death (necroptosis) [26-28].
- Selenite has been shown to increase the in vivo effect of cisplatin in the A2780 tumor model [29].
- alpha-lipoic acid and sodium-sulfite have not resulted in a synergistic increase of antitumor activity (see example 11), thus excluding the possibility that a redox reaction between alpha-lipoic acid and the selenite anion taking place in the cell culture media would account for the synergism of alpha-lipoic acid and sodium-selenite.
- dihydrolipoic acid is formed intracellularly in the human body from alpha-lipoic acid, it is not a stable compound (it is easily oxidized), therefore its application in a composition according to the invention is not expedient.
- alpha-lipoic acid and sodium-selenite can be further increased in a synergistic manner by the individual combination of the following active substances with a mixture of alpha-lipoic acid and sodium-selenite: L-tryptophan, D-tryptophan, L-methionine, D-phenylalanine, agmatine, phenylpyruvic acid, gentisic acid, pyrrole-2-carboxylic acid (see examples 18-25).
- chemotherapeutic substances e.g. docetaxel, doxorubicin, taxane-derivatives, cisplatin etc.
- docetaxel, doxorubicin, taxane-derivatives, cisplatin etc. which in general have serious toxicity, during a chemotherapeutic treatment became achievable with our invention.
- the invention relates to therapeutical compositions for the prevention and treatment of neoplastic disorders and uses thereof.
- the subject matter of the invention is a synergistic composition containing exclusively lipoic acid or a therapeutically acceptable salt thereof and selenite as the primary active substances, optionally in conjunction with one or more secondary active substance(s) with a maximal molecular weight of 280 daltons, and optionally in conjunction with one or more usual therapeutically acceptable carrier(s), diluent(s) and/or other excipient(s).
- the composition contains exclusively the above mentioned primary active substances.
- the composition in addition to the two primary active substances, comprises exclusively one or more secondary active substance(s) mentioned in points 4 and 5 below.
- the composition may also comprise one or more usual pharmaceutical excipient(s) without a therapeutic effect (e.g. usual therapeutically acceptable carriers, diluents and/or other excipients).
- synergistic composition comprising one or more compound(s) as secondary active substance(s) selected form the following group: L- tryptophan, D-tryptophan, L-methionine, D-phenylalanine, agmatine, phenylpyruvic acid, gentisic acid, pyrrole-2-carboxylic acid, L-arginine, D-arginine, L-phenylalanine, L-histidine, L-tyrosine, pyridoxine, D(+)-biotin, L(+)-ascorbic acid, L(-)-malic acid, D-(+)-glucosamine, ketoisocaproic acid (4-methyl-2-oxovaleric acid), cinnamic acid, adenosine, melatonin, p- coumaric acid and therapeutically acceptable salts thereof.
- synergistic composition according to point 4 comprising one or more compound(s) as secondary active substance(s) selected form the following group: L- tryptophan, D-tryptophan, L-methionine, D-phenylalanine, agmatine, phenylpyruvic acid, gentisic acid, pyrrole-2-carboxylic acid and therapeutically acceptable salts thereof.
- synergistic composition according to any of points 1-5 for use in the prevention or treatment of neoplastic disorders in mammals, particularly in humans.
- a method for the prevention or treatment of neoplastic disorders characterized by that the patient in need of treatment is administered a synergistic composition according to any of points 1-5 in a therapeutically effective amount, preferably in an amount of 5-500 mg per kg body weight in 1-15 portion(s) per day.
- Figure 1 dose-antitumor effect curves obtained on HELA cells with ( ⁇ )- alpha-lipoic acid applied in 0.5 mM, 0.4 mM, 0.3 mM concentrations, with sodium-selenite applied in 1 ⁇ , 0.75 ⁇ , 0.5 ⁇ concentrations, and with the combined application of the two compounds in the above concentrations.
- Figure 1. part “B” plot of the antitumor effect on a normalized isobologram [34] obtained on HELA cells with the combined application of ( ⁇ )-alpha-lipoic (LA) acid and sodium-selenite (SEL) in the indicated concentrations.
- LA normalized isobologram
- Figure 2. part “A” dose-antitumor effect curves obtained on HELA cells with ( ⁇ )- alpha-lipoic acid applied in 0.5 mM, 0.4 mM, 0.3 mM concentrations, with sodium-selenite applied in 4 ⁇ , 3 ⁇ , 2 ⁇ concentrations, and with the combined application of the two compounds in the above concentrations.
- Figure 1. part “B” plot of the antitumor effect on a normalized isobologram obtained on HELA cells with the combined application of ( ⁇ )-alpha- lipoic (LA) acid and sodium-selenite (SEL) in the indicated concentrations.
- Figure 3 in vivo antitumor effect obtained on the C26 tumor model with ( ⁇ )-alpha- lipoic acid (LA) applied per se in a dose of 50mg/kg, with sodium-selenite applied per se in a dose of 1.5 mg/kg, and with the combined application of the two compounds in the above doses (LA+SEL).
- Part "A” tumor volumes measured during the treatment period (*p ⁇ 0,001 vs. CTRL, vs. LA, vs. SEL).
- Part “B” tumor weights measured on the 10 th day of the treatment (*p ⁇ 0,05 vs. CTRL, vs. LS; #p ⁇ 0,001 vs. SEL).
- lipoic acid designates racemic lipoic acid [( ⁇ )-alpha-lipoic acid, which represents a preferred embodiment], and in addition enantiomers thereof [(+)-alpha-lipoic acid and (-)-alpha-lipoic acid], or any mixtures thereof.
- the lipoic acid can be applied in the form of a salt, consequent from the intended use obviously in the form of a therapeutically acceptable salt.
- the cation present in the salt can be derived from an organic or inorganic acid.
- Preferred examples are salts formed with alkali metal and alkaline earth metal cations, or with a quaternary ammonium cation (or with other quaternary nitrogen-containing cation).
- alkali metal and alkaline earth metal salts more preferred is the sodium salt.
- the term "selenite” used alone designates a salt derived from selenous acid (thus in this general name we refer to the salt, for the sake of simplicity, with the name of the anion present in it).
- the cation can be an alkali metal and alkaline earth metal cation, or a quaternary ammonium cation (or other quaternary nitrogen-containing cation).
- these salts particularly preferred are the following selenites: sodium-selenite, potassium-selenite, magnesium-selenite and calcium-selenite, particularly preferred is the sodium-selenite.
- the ratio of the active substances is given as mass ratio.
- the mass ratios and mass percentage values in case of therapeutically acceptable salts of the listed active substances refer to the free bases/acids.
- the mass ratio of the primary active substances can vary in a wide range, however it is typical, that the lipoic acid is present in a substantially higher amount than selenite.
- the mass ratio of lipoic acid:selenite falls into the range of 10-10000: 1, preferably into the range of 50-5000: 1, more preferably into the range of 100- 3000: 1.
- the group of secondary active substances does not include the conventionally applied high molecular weight chemotherapeutic compounds (such as e.g. cisplatin, doxorubicin, etoposide, paclitaxel, irinotecan HCL, vincristine).
- the group of secondary active substances includes compounds with a maximal molecular weight of 280 daltons (the compounds are typically acids).
- Preferred cases of such compounds are the following: L-tryptophan, D-tryptophan, L-methionine, D-phenylalanine, agmatine, phenylpyruvic acid, gentisic acid, pyrrole-2-carboxylic acid, L-arginine, D-arginine, L- phenylalanine, L-histidine, L-tyrosine, pyridoxine, D(+)-biotin, L(+)-ascorbic acid, L(-)-malic acid, D-(+)-glucosamine, ketoisocaproic acid (4-methyl-2-oxovaleric acid), cinnamic acid, adenosine, melatonin, p-coumaric acid and therapeutically acceptable salts of said compounds.
- More preferred secondary active substances are the following: L-tryptophan, D- tryptophan, L-methionine, D-phenylalanine, agmatine, phenylpyruvic acid, gentisic acid, pyrrole-2-carboxylic acid and therapeutically acceptable salts of said compounds.
- the secondary active substances are also typically applied in a high mass ratio compared to the selenite (if salts are applied then the calculation is also based on the free base/acid form of the substances).
- the mass ratio of the "secondary active substance": selenite falls into the range of 10-10000: 1, preferably into the range of 50- 5000: 1, more preferably into the range of 100-3000: 1.
- composition designates preferably a therapeutical composition, which may comprise usual therapeutically/pharmaceutically acceptable excipients (see in more detail below). However, the composition can also be formulated as a dietary supplement or foodstuff.
- the active substances according to the invention and their therapeutically acceptable salts, and the therapeutical compositions made from them can be administered in any ordinary way. They can be used for example orally, parenterally (including subcutaneous, intramuscular and intravenous administration), buccally, sublingually, nasally, rectally or transdermally.
- the therapeutical compositions are prepared in unit dosage form using the ordinary pharmaceutical procedures, the usual therapeutically/pharmaceutically acceptable carriers, diluents and/or other excipients.
- the active substances according to the invention define the active substances according to the invention and/or therapeutically acceptable salts thereof.
- compositions containing active substances according to the invention that are orally active can be prepared in a liquid or solid form.
- active substances according to the invention that are orally active
- syrup, suspension, emulsion, tablets, capsules or lozenges can be prepared.
- the active substances according to the invention are prepared in liquid form, for example as a suspension solution, it will contain the active substances according to the invention in a suitable liquid carrier or carriers.
- Aqueous solvents e.g. water, ethanol or glycerine
- non-aqueous solvents e.g. polyethylene glycol or some sort of oil
- the composition may also comprise suspending agents, preservatives, flavouring and colouring agents.
- the solid composition is a tablet, it can be formulated with any suitable carrier routinely used in the preparation of medicaments.
- Solid carriers can be for example lactose, suitable silicates, sucrose, talcum, gelatine, agar, pectin, gum arabic, magnesium stearate and stearic acid, etc.
- a standard aqueous or non-aqueous coating can be applied on the tablets.
- tablets can be prepared by pressing or moulding, optionally using one or more absorption promoting agents or adjuvants.
- Tablets can be manufactured for example by means of a suitable tablet press machine; the active substance can be pressed in powder or granular form, optionally mixed with excipients, lubricants, inert diluents, surface active or dispersive agents.
- the solid composition is a capsule, it can be manufactured using any ordinary encapsulation method.
- pellets can be made from the active substances combined with a standard carrier, and then they can be filled in hard gelatine capsules.
- a dispersion or suspension can be prepared from the active substances combined with a suitable pharmaceutical carrier, and then it can be filled in soft gelatine capsules.
- suitable pharmaceutical carriers can be for example water-dispersible gums, cellulose, silicates or oils.
- parenteral compositions are solutions or suspensions which contain the active substances according to the invention in sterile aqueous carriers or parentally administrable non-aqueous carriers, e.g. in polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil.
- sterile aqueous carriers or parentally administrable non-aqueous carriers e.g. in polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil.
- the solution can be lyophilized, and directly before administration it is transformed into a solution again with a suitable solvent.
- compositions according to the invention suitable for nasal administration contain the active substances according to the invention in aerosols, drops, gel or powder form.
- the aerosols according to the invention contain the active substances according to the invention typically in a solution or a finely dispersed suspension, in a physiologically acceptable aqueous or non-aqueous solvent.
- the sterile aerosol can be packaged in a closed container containing a single dose or several doses, which container enables administration or refilling and is generally equipped with a nebuliser.
- the closed container may also be suitable for the administration of unit doses; for example it can be an inhaler ensuring single doses, or an aerosol dispenser with a dispensing valve, which can be disposed of when the container is empty.
- a propellant e.g. a compressed gas (e.g. compressed air) or an organic propellant (e.g. chlorinated/fluorinated hydrocarbons) can be used.
- a nebuliser pump e.g. a nebuliser pump.
- compositions according to the invention containing the active substances according to the invention are also suitable for buccal and sublingual administration, for example in the form of tablets, lozenges or pastilles; they contain the active substances formulated with a carrier (e.g. sugar and gum arabic, tragacanth, or gelatine, glycerine, etc.).
- a carrier e.g. sugar and gum arabic, tragacanth, or gelatine, glycerine, etc.
- composition containing the active substances according to the invention is also suitable for rectal administration.
- suppositories are prepared, which contain the active substances in a suppository base such as cocoa butter or some other known carrier. Suppositories are prepared by usual method, by mixing the components, then softening and melting the mixture and pouring the melt into a mould and cooling it.
- composition containing the active substances according to the invention is also suitable for transdermal administration, e.g. in the form of an ointment, gel or plaster.
- the daily dose of the composition according to the invention is influenced by numerous factors such as the kind of the disease to be treated, the condition of the patient, the other ongoing treatments, the route of administration etc.
- a composition comprising 5-500 mg, preferably 10-300 mg active substances per kg adult body weight, should be administered daily.
- the daily dose should be administered in 1-15 portion(s) in the form of tablet, capsule, pill, drink powder, solution for infusion etc.
- the suitable daily dose has been determined for mammals, specifically for humans.
- the different types of cancer cells e.g. with different histological origin and type
- the metabolism of which differ from the normal cells at different extent can show a various degree of sensitivity to combinations of the active substances according to the invention.
- the qualitative and quantitative composition of the mixtures described in the present invention can be optimized for the given type of cancer by using the synergism as selection criterion.
- the sensitivity of cancer cells isolated from the tumor tissue of a given individual to a composition according to the invention can also be determined, and the composition of the mixtures can be optimized (individualized therapy).
- the composition according to the invention can be preferably used for the prevention and treatment of the following neoplastic disorders: malignant (cancerous) tumors, such as malignant neoplasms of lip, oral cavity and pharynx, malignant neoplasms of digestive organs, malignant neoplasms of respiratory and intrathoracic organs, malignant neoplasms of bone and articular cartilage, melanoma and other malignant neoplasms of skin, malignant neoplasms of mesothelial and soft tissue, malignant neoplasm of breast, malignant neoplasms of female genital organs, malignant neoplasms of male genital organs, malignant neoplasms of urinary tract, malignant neoplasms of eye, brain and other parts of central nervous system, malignant neoplasms of thyroid and other endocrine glands, malignant neoplasms of ill- defined, secondary and unspec
- TELA American Type Culture Collection, product number: CCL-2
- HELA American Type Culture Collection, product number: CCL-2
- HELA High Efficiency Culture Collection
- MEM media Sigma-Aldrich, product number: M2279
- CI combination index
- the value of the CI is between 0.85 and 0.90 then slight synergism; if the value of the CI is between 0.7 and 0.85 then moderate synergism; if the value of the CI is between 0.3 and 0.7 then synergism; if the value of the CI is between 0.1 and 0.3 then strong synergism; if the value of the CI ⁇ 0.1 then very strong synergism is present.
- Dl and D2 are the doses of the two compounds in the D1+D2 combination which produce an inhibition of X%, while ⁇ and ⁇ 2 represents the doses of the two compounds which produce an inhibition of X% when the two compounds are applied per se. If the data points on the normalized isobologram are localized lower-left from the line connecting the ends of the two axes then synergism is present, if data points are localized along the connecting line then the effect of the two compounds is additive, and if data points are localized upper-right from the connecting line then antagonism is present.
- the normalized isobologram shown in Figure 1 part "B" confirms that there is synergism in the antitumor effect between LA and sodium-selenite at the investigated concentrations.
- TGI tumor growth
- TGI values calculated on the basis of tumor volumes were the following: 25.8%, 34.4%, 23.3% on the 6 th , 8 th and 10 th days of the treatment, respectively.
- the TGI calculated on the basis of tumor weight was 35.2%), p ⁇ 0.05 vs. control and vs. LA applied per se, p ⁇ 0.001 vs. sodium-selenite applied per se.
- the result of the experiment provides in vivo confirmation of the in vitro demonstrated synergistic antitumor effect of LA and sodium-selenite.
- Enantiomers of alpha-lipoic acid applied individually at 0.5 mM, 0.4 mM, 0.3 mM concentrations in combination with 1 ⁇ , 0.75 ⁇ , 0.5 ⁇ concentrations of sodium-selenite produce a synergistic antitumor effect on HELA cells.
- synergistic antitumor activity seen upon the combined application of alpha-lipoic acid and sodium-selenite is not caused by reactive oxygen species formed from sodium-selenite in the cell culture media triggered by free SH-groups formed during the incidental reduction of alpha-lipoic acid, since if this would be the case we should have obtained a synergistic antitumor effect upon the combination of free SH-group containing compounds other than LA (reduced L-glutathione and L-cysteine) with sodium-selenite.
- L-tryptophan synergistically enhances the antitumor effect of the mixture of ( ⁇ )-alpha-lipoic acid and sodium- selenite on HELA cells
- D-tryptophan synergistically enhances the antitumor effect of the mixture of ( ⁇ )-alpha-lipoic acid and sodium- selenite on HELA cells
- L-methionine synergistically enhances the antitumor effect of the mixture of ( ⁇ )-alpha-lipoic acid and sodium- selenite on HELA cells
- D-phenylalanine synergistically enhances the antitumor effect of the mixture of ( ⁇ )-alpha-lipoic acid and sodium-selenite on HELA cells
- Agmatine-sulfate synergistically enhances the antitumor effect of the mixture of ( ⁇ )-alpha-lipoic acid and sodium-selenite on HELA cells
- sodium-phenylpyruvate synergistically enhances the antitumor effect of the mixture of LA and sodium-selenite, and the simultaneous presence of both LA and sodium-selenite is necessary for the occurrence of this synergism.
- Pyrrole-2-carboxylic acid synergistically enhances the antitumor effect of the mixture of ( ⁇ )-alpha-lipoic acid and sodium-selenite on HELA cells
- Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization, Biofactors 6 (1997) 321-338. [6] U.Wenzel, A. Nickel, H. Daniel, Alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant 02-*- generation, Apoptosis 10 (2005) 359-368.
- Nonredox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo, J. Mol. Med. (Berl.) 89 (2011) 1137-1148.
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Abstract
L'objet de l'invention est une composition synergique contenant exclusivement de l'acide lipoïque ou un sel thérapeutiquement acceptable dudit composé et de la sélénite en tant que substances actives primaires, facultativement en association avec une ou plusieurs substance(s) active(s) secondaire(s) avec un poids moléculaire maximal de 280 daltons, et facultativement en association avec un ou plusieurs support(s), diluant(s) et/ou autre(s) excipient(s) usuels thérapeutiquement acceptables.
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